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Predicting the interaction between Major Histocompatibility Complex (MHC) class I-presented peptides and T-cell receptors (TCR) holds significant implications for vaccine development, cancer treatment, and autoimmune disease therapies. However, limited paired-chain TCR data, skewed towards well-studied epitopes, hampers the development of pan-specific machine-learning (ML) models. Leveraging a larger peptide-TCR dataset, we explore various alterations to the ML architectures and training strategies to address data imbalance. This leads to an overall improved performance, particularly for peptides with scant TCR data. However, challenges persist for unseen peptides, especially those distant from training examples. We demonstrate that such ML models can be used to detect potential outliers, which when removed from training, leads to augmented performance. Integrating pan-specific and peptide-specific models alongside with similarity-based predictions, further improves the overall performance, especially when a low false positive rate is desirable. In the context of the IMMREP22 benchmark, this modeling framework attained state-of-the-art performance. Moreover, combining these strategies results in acceptable predictive accuracy for peptides characterized with as little as 15 positive TCRs. This observation places great promise on rapidly expanding the peptide covering of the current models for predicting TCR specificity. The NetTCR 2.2 model incorporating these advances is available on GitHub (https://github.com/mnielLab/NetTCR-2.2) and as a web server at https://services.healthtech. dtu.dk/services/NetTCR-2.2/. [ABSTRACT FROM AUTHOR]

Herpesvirus of turkey (HVT) increases activation of T cells in 1-day-old chickens when administered in ovo. This study evaluated whether adding cytosine-guanosine oligodeoxynucleotides (CpG ODNs) to the HVT vaccine could enhance the adjuvant effect of HVT. We used a CpG ODN dose of 10 μg per egg. The experimental groups were (1) diluent-only control (sham), (2) HVT, (3) HVT+CpG ODN, (4) HVT+non-CpG ODN, (5) CpG ODN, and (6) non-CpG ODN control. Cellular response evaluation included measuring the frequencies of macrophages (KUL01+MHC-II+), gamma delta T cells (γδTCR+MHC-II+), CD4+, and CD8+ T cell subsets, including double-positive (DP) cells. In addition, CD4+ and CD8+ T cell activation was evaluated by measuring the cellular expression of major histocompatibility complex class II (MHC-II), CD44 or CD28 costimulatory molecules. An adjuvant effect was considered when HVT+CpG ODN, but not HVT+non CpG ODN, or CpG ODN, or non-CpG ODN, induced significantly increased effects on any of the immune parameters examined when compared with HVT. The findings showed that (1) HVT vaccination induced significantly higher frequencies of γδ+MHC-II+ and CD4+CD28+ T cells when compared with sham chickens. Frequencies of DP and CD4+CD28+ T cells in HVT-administered birds were significantly higher than those observed in the non-CpG ODN group. (2) Groups receiving HVT+CpG ODN or CpG ODN alone were found to have significantly increased frequencies of activated CD4+ and CD8+ T cells, when compared with HVT. Our results show that CpG ODN administration in ovo with or without HVT significantly increased frequencies of activated CD4+ and CD8+ T cells. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) encodes a range of immune response genes, including the human leukocyte antigens (HLAs) in humans. These molecules bind peptide antigens and present them on the cell surface for T cell recognition. The repertoires of peptides presented by HLA molecules are termed immunopeptidomes. The highly polymorphic nature of the genres that encode the HLA molecules confers allotype-specific differences in the sequences of bound ligands. Allotype-specific ligand preferences are often defined by peptide-binding motifs. Individuals express up to six classical class I HLA allotypes, which likely present peptides displaying different binding motifs. Such complex datasets make the deconvolution of immunopeptidomic data into allotype-specific contributions and further dissection of binding-specificities challenging. Herein, we developed MHCpLogics as an interactive machine learning-based tool for mining peptide-binding sequence motifs and visualization of immunopeptidome data across complex datasets. We showcase the functionalities of MHCpLogics by analyzing both in-house and published mono- and multi-allelic immunopeptidomics data. The visualization modalities of MHCpLogics allow users to inspect clustered sequences down to individual peptide components and to examine broader sequence patterns within multiple immunopeptidome datasets. MHCpLogics can deconvolute large immunopeptidome datasets enabling the interrogation of clusters for the segregation of allotype-specific peptide sequence motifs, identification of sub-peptidome motifs, and the exportation of clustered peptide sequence lists. The tool facilitates rapid inspection of immunopeptidomes as a resource for the immunology and vaccine communities. MHCpLogics is a standalone application available via an executable installation at: https://github.com/PurcellLab/MHCpLogics. [ABSTRACT FROM AUTHOR]

Neoantigens are derived from somatic mutations in the tumors but are absent in normal tissues. Emerging evidence suggests that neoantigens can stimulate tumor-specific T-cell-mediated antitumor immune responses, and therefore are potential immunotherapeutic targets. We developed ImmuneMirror as a stand-alone open-source pipeline and a web server incorporating a balanced random forest model for neoantigen prediction and prioritization. The prediction model was trained and tested using known immunogenic neopeptides collected from 19 published studies. The area under the curve of our trained model was 0.87 based on the testing data. We applied ImmuneMirror to the whole-exome sequencing and RNA sequencing data obtained from gastrointestinal tract cancers including 805 tumors from colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma patients. We discovered a subgroup of microsatellite instability-high (MSI-H) CRC patients with a low neoantigen load but a high tumor mutation burden (> 10 mutations per Mbp). Although the efficacy of PD-1 blockade has been demonstrated in advanced MSI-H patients, almost half of such patients do not respond well. Our study identified a subset of MSI-H patients who may not benefit from this treatment with lower neoantigen load for major histocompatibility complex I (P  < 0.0001) and II (P  = 0.0008) molecules, respectively. Additionally, the neopeptide YMCNSSCMGV-TP53G245V, derived from a hotspot mutation restricted by HLA-A02, was identified as a potential actionable target in ESCC. This is so far the largest study to comprehensively evaluate neoantigen prediction models using experimentally validated neopeptides. Our results demonstrate the reliability and effectiveness of ImmuneMirror for neoantigen prediction. [ABSTRACT FROM AUTHOR]

Objective: To observe the regulatory effect of microRNA-10b (miR-10b) on the immune effect of glioma cells and explore its mechanism. Methods: Human glioma cell U251 was cultured to obtain cells in logarithmic growth stage. The cell suspension was prepared according to the concentration of 1.0x105 cells/ml, and the control group, overexpression group, low expression group and blank group were set up, with 6 wells in each group. The negative control, miR-10b mimics and miR-10b inhibitor were transfected by liposome transfection in control group, overexpression group and low expression group, respectively. The blank group was given the same amount of sterile normal saline. Natural killer (NK) cells from peripheral blood of a healthy volunteer was isolated and cultured. The killing activity of NK cells was detected by MTT method. The expression of NK cell activated receptor (NKG2D) on the surface of NK cells in each group were detected by flow cytometry, and the expression of major histocompatibility complex class I chain-related gene A (MICA), UL16 binding protein 2 (ULBP2) and UL16 binding protein 3 (ULBP3) on the surface of U251 human glioma cells in each group were detected. Results: The transfection efficiency of control group, overexpression group and low ex-pression group were (93.55±2.05)%, (95.67±3.14)%, (94.18±3.26)%, respectively. Compared with control group and blank group, the expression of miR-10b increased in overexpression group and decreased in low expression group, and the difference were statistically significant (P<0.05). There was no significant difference in the expression of miR-10b between control group and blank group (P>0.05). Compared with control group and blank group, the killing activity of NK cells with different effect target ratios in overexpression group decreased, the expression of NKG2D decreased, the killing activity of NK cells with different effect target ratios in low expression group increased, and the expression of NKG2D increased, and the difference were statistically significant (P<0.05). The killing activity of NK cells in each group increased with the increase of effect target ratio, and the difference were statistically significant (P<0.05), and there was no significant difference in NK cell killing activity and NKG2D expression between control group and blank group (P>0.05). Compared with control group and blank group, the expression of MICA, ULBP2 and ULBP3 on the surface of human glioma cell U251 in overexpression group decreased, and the expression of MICA, ULBP2 and ULBP3 on the surface of human glioma cell U251 in low expression group increased, the difference were statistically significant (P<0.05), and there was no significant difference in the expression of MICA, ULBP2 and ULBP3 on the surface of U251 glioma cells between control group and blank group (P>0.05). Conclusion: Inhibiting the expression of miR-10b can increase the expression of NKG2D on the surface of NK cells and MICA, ULBP2 and ULBP3 on the surface of human glioma cell U251, and enhance the killing activity of NK cells against human glioma cell U251. [ABSTRACT FROM AUTHOR]

T cell is vital in the adaptive immune system, which relays on T-cell receptor (TCR) to recognize and defend against infection and tumors. T cells are mainly divided into well-known CD4+ and CD8+ T cells, which can recognize short peptide antigens presented by major histocompatibility complex (MHC) class II and MHC class I respectively in humoral and cell-mediated immunity. Due to the Human Leukocyte Antigen (HLA) diversity and restriction with peptides complexation, TCRs are quite diverse and complicated. To better elucidate the TCR in humans, the present study shows the difference between the TCR repertoire in CD4+ and CD8+ T cells from 30 healthy donors. The result showed count, clonality, diversity, frequency, and VDJ usage in CD4+ and CD8+ TCR-β repertoire is different, but CDR3 length is not. The Common Clone Cluster result showed that CD4+ and CD8+ TCR repertoires are connected separately between the bodies, which is odd considering the HLA diversity. More knowledge about TCR makes more opportunities for immunotherapy. The TCR repertoire is still a myth for discovery. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) seems to play causative roles in gastric cancers. H. pylori has also been detected in established gastric cancers. How the presence of H. pylori modulates immune response to the cancer is unclear. The cytotoxicity of natural killer (NK) cells, toward infected or malignant cells, is controlled by the repertoire of activating and inhibitory receptors expressed on their surface. Here, we studied H. pylori‐induced changes in the expression of ligands, of activating and inhibitory receptors of NK cells, in the gastric adenocarcinoma AGS cells, and their impacts on NK cell responses. AGS cells lacked or had low surface expression of the class I major histocompatibility complex (MHC‐I) molecules HLA‐E and HLA‐C—ligands of the major NK cell inhibitory receptors NKG2A and killer‐cell Ig‐like receptor (KIR), respectively. However, AGS cells had high surface expression of ligands of activating receptors DNAM‐1 and CD2, and of the adhesion molecules LFA‐1. Consistently, AGS cells were sensitive to killing by NK cells despite the expression of inhibitory KIR on NK cells. Furthermore, H. pylori enhanced HLA‐C surface expression on AGS cells. H. pylori infection enhanced HLA‐C protein synthesis, which could explain H. pylori‐induced HLA‐C surface expression. H. pylori infection enhanced HLA‐C surface expression also in the hepatoma Huh7 and HepG2 cells. Furthermore, H. pylori‐induced HLA‐C surface expression on AGS cells promoted inhibition of NK cells by KIR, and thereby protected AGS cells from NK cell cytotoxicity. These results suggest that H. pylori enhances HLA‐C expression in host cells and protects them from the cytotoxic attack of NK cells expressing HLA‐C‐specific inhibitory receptors. [ABSTRACT FROM AUTHOR]

Adoptive T cell immunotherapies, including engineered T cell receptor (eTCR) and chimeric antigen receptor (CAR) T cell immunotherapies, have shown efficacy in treating a subset of hematologic malignancies, exhibit promise in solid tumors, and have many other potential applications, such as in fibrosis, autoimmunity, and regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues to manipulate T cells ex vivo and in vivo, mechanical cues that regulate their biology have been largely underappreciated. This review highlights the contributions of mechanical force to several receptor–ligand interactions critical to T cell function, with central focus on the TCR–peptide-loaded major histocompatibility complex (pMHC). We then emphasize the role of mechanical forces in (i) allosteric strengthening of the TCR–pMHC interaction in amplifying ligand discrimination during T cell antigen recognition prior to activation and (ii) T cell interactions with the extracellular matrix. We then describe approaches to design eTCRs, CARs, and biomaterials to exploit TCR mechanosensitivity in order to potentiate T cell manufacturing and function in adoptive T cell immunotherapy. [ABSTRACT FROM AUTHOR]

Background The role of macrophages in the development of rhabdomyolysis-induced acute kidney injury (RM-AKI) has been established, but an in-depth understanding of the changes in the immune landscape could help to improve targeted strategies. Whereas senescence is usually associated with chronic kidney processes, we also wished to explore whether senescence could also occur in AKI and whether senolytics could act on immune cells. Methods Single-cell RNA sequencing was used in the murine glycerol-induced RM-AKI model to dissect the transcriptomic characteristics of CD45+ live cells sorted from kidneys 2 days after injury. Public datasets from murine AKI models were reanalysed to explore cellular senescence signature in tubular epithelial cells (TECs). A combination of senolytics (dasatinib and quercetin, DQ) was administered to mice exposed or not to RM-AKI. Results Unsupervised clustering of nearly 17 000 single-cell transcriptomes identified seven known immune cell clusters. Sub-clustering of the mononuclear phagocyte cells revealed nine distinct cell sub-populations differently modified with RM. One macrophage cluster was particularly interesting since it behaved as a critical node in a trajectory connecting one major histocompatibility complex class IIhigh (MHCIIhigh) cluster only present in Control to two MHCIIlow clusters only present in RM-AKI. This critical cluster expressed a senescence gene signature, that was very different from that of the TECs. Senolytic DQ treatment blocked the switch from a F4/80highCD11blow to F4/80lowCD11bhigh phenotype, which correlated with prolonged nephroprotection in RM-AKI. Conclusions Single-cell RNA sequencing unmasked novel transitional macrophage subpopulation associated with RM-AKI characterized by the activation of cellular senescence processes. This work provides a proof-of-concept that senolytics nephroprotective effects may rely, at least in part, on subtle immune modulation. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even in an allogeneic setting. Despite this tremendous potential, challenges persist, such as limited in vivo persistence, reduced tumor infiltration, and low absolute NK cell numbers. This review outlines several strategies aiming to overcome these challenges. The developed strategies include optimizing NK cell expansion methods and improving NK cell antitumor responses by cytokine stimulation and genetic manipulations. Using K562 cells expressing membrane IL-15 or IL-21 with or without additional activating ligands like 4-1BBL allows "massive" NK cell expansion and makes multiple cell dosing and "off-the-shelf" efforts feasible. Further improvements in NK cell function can be reached by inducing memory-like NK cells, developing chimeric antigen receptor (CAR)-NK cells, or isolating NK-cell-based tumor-infiltrating lymphocytes (TILs). Memory-like NK cells demonstrate higher in vivo persistence and cytotoxicity, with early clinical trials demonstrating safety and promising efficacy. Recent trials using CAR-NK cells have also demonstrated a lack of any major toxicity, including cytokine release syndrome, and, yet, promising clinical activity. Recent data support that the presence of TIL-NK cells is associated with improved overall patient survival in different types of solid tumors such as head and neck, colorectal, breast, and gastric carcinomas, among the most significant. In conclusion, this review presents insights into the diverse strategies available for NK cell expansion, including the roles played by various cytokines, feeder cells, and culture material in influencing the activation phenotype, telomere length, and cytotoxic potential of expanded NK cells. Notably, genetically modified K562 cells have demonstrated significant efficacy in promoting NK cell expansion. Furthermore, culturing NK cells with IL-2 and IL-15 has been shown to improve expansion rates, while the presence of IL-12 and IL-21 has been linked to enhanced cytotoxic function. Overall, this review provides an overview of NK cell expansion methodologies, highlighting the current landscape of clinical trials and the key advancements to enhance NK-cell-based adoptive cell therapy. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) capture pathogens and process antigens, playing a crucial role in activating naïve T cells, bridging the gap between innate and acquired immunity. However, little is known about DC activation when facing Leishmania parasites. Thus, this study investigates in vitro activity of canine peripheral blood-derived DCs (moDCs) exposed to L. infantum and L. amazonensis parasites and their extracellular vesicles (EVs). L. infantum increased toll-like receptor 4 gene expression in synergy with nuclear factor κB activation and the generation of pro-inflammatory cytokines. This parasite also induced the expression of class II molecules of major histocompatibility complex (MHC) and upregulated co-stimulatory molecule CD86, which, together with the release of chemokine CXCL16, can attract and help in T lymphocyte activation. In contrast, L. amazonensis induced moDCs to generate a mix of pro- and anti-inflammatory cytokines, indicating that this parasite can establish a different immune relationship with DCs. EVs promoted moDCs to express class I MHC associated with the upregulation of co-stimulatory molecules and the release of CXCL16, suggesting that EVs can modulate moDCs to attract cytotoxic CD8+ T cells. Thus, these parasites and their EVs can shape DC activation. A detailed understanding of DC activation may open new avenues for the development of advanced leishmaniasis control strategies. [ABSTRACT FROM AUTHOR]

Antigen-presentation via major histocompatibility complex (MHC) to T cells is the key event to initiate adaptive immune responses. In teleosts, as in mammals, the main types of professional antigen-presenting cells (APCs) are dendritic cells (DCs), monocytes/macrophages, and B cells. In the current study, flow cytometry, immunostaining and qPCR have been used to show that neutrophils in the teleost fish Atlantic salmon (Salmo salar L.) have antigen-presenting properties. The neutrophils were positive for MHC class II, CD83 and CD80/86, and upon in vitro bacterial exposure, gene expression analysis of purified neutrophils showed that IL-12p40, which is essential for proliferation of naïve T cells, was highly upregulated at both 6 and 24 h post bacterial exposure. Based on presence of MHC class II and upregulation of molecules involved in antigen presentation and T cell activation, we suggest that neutrophils in Atlantic salmon have potential to function as professional APCs. This work makes an important basis for further exploring the potential of using neutrophils to develop new, targeted immunoprophylactic measures. [ABSTRACT FROM AUTHOR]

Superantigens, i.e., staphylococcal enterotoxins and toxic shock syndrome toxin-1, interact with T cells in a different manner in comparison to conventional antigens. In fact, they activate a larger contingent of T lymphocytes, binding outside the peptide-binding groove of the major histocompatibility complex class II. Involvement of many T cells by superantigens leads to a massive release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma. Such a storm of mediators has been shown to account for tissue damage, multiorgan failure and shock. Besides conventional drugs and biotherapeutics, experiments with natural and biological products have been undertaken to attenuate the toxic effects exerted by superantigens. In this review, emphasis will be placed on polyphenols, probiotics, beta-glucans and antimicrobial peptides. In fact, these substances share a common functional denominator, since they skew the immune response toward an anti-inflammatory profile, thus mitigating the cytokine wave evoked by superantigens. However, clinical applications of these products are still scarce, and more trials are needed to validate their usefulness in humans. [ABSTRACT FROM AUTHOR]

Capsid assembly is critical in the hepatitis B virus (HBV) life cycle, mediated by the viral core protein. Capsid assembly is the target for new anti-viral therapeutics known as capsid assembly modulators (CAMs) of which the CAM-aberrant (CAM-A) class induces aberrant shaped core protein structures and leads to hepatocyte cell death. This study aimed to identify the mechanism of action of CAM-A modulators leading to HBV-infected hepatocyte elimination where CAM-A-mediated hepatitis B surface antigen (HBsAg) reduction was evaluated in a stable HBV replicating cell line and in AAV-HBV-transduced C57BL/6, C57BL/6 SCID, and HBV-infected chimeric mice with humanized livers. Results showed that in vivo treatment with CAM-A modulators induced pronounced reductions in hepatitis B e antigen (HBeAg) and HBsAg, associated with a transient alanine amino transferase (ALT) increase. Both HBsAg and HBeAg reductions and ALT increase were delayed in C57BL/6 SCID and chimeric mice, suggesting that adaptive immune responses may indirectly contribute. However, CD8+ T cell depletion in transduced wild-type mice did not impact antigen reduction, indicating that CD8+ T cell responses are not essential. Transient ALT elevation in AAV-HBV-transduced mice coincided with a transient increase in endoplasmic reticulum stress and apoptosis markers, followed by detection of a proliferation marker. Microarray data revealed antigen presentation pathway (major histocompatibility complex class I molecules) upregulation, overlapping with the apoptosis. Combination treatment with HBV-specific siRNA demonstrated that CAM-A-mediated HBsAg reduction is dependent on de novo core protein translation. To conclude, CAM-A treatment eradicates HBV-infected hepatocytes with high core protein levels through the induction of apoptosis, which can be a promising approach as part of a regimen to achieve functional cure. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a hematological tumor with high mortality and recurrence rate. Carfilzomib is a new-generation proteasome inhibitor that is used as the first-line therapy for MM. However, the development of drug resistance is a pervasive obstacle to treating MM. Therefore, elucidating the drug resistance mechanisms is conducive to the formulation of novel therapeutic therapies. To elucidate the mechanisms of carfilzomib resistance, we retrieved the GSE78069 microarray dataset containing carfilzomib-resistant LP-1 MM cells and parental MM cells. Differential gene expression analyses revealed major alterations in the major histocompatibility complex (MHC) and cell adhesion molecules. The upregulation of the tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) gene was accompanied by the downregulation of MHC genes and cell adhesion molecules. Furthermore, to investigate the roles of these genes, we established a carfilzomib-resistant cell model and observed that carfilzomib resistance induced TNFRSF1A overexpression and TNFRSF1A silencing reversed carfilzomib resistance and reactivated the expression of cell adhesion molecules. Furthermore, TNFRSF1A silencing suppressed the tumorigenesis of MM cells in immunocompetent mice, indicating that TNFRSF1A may lead to carfilzomib resistance by dampening antitumor immunity. Furthermore, our results indicated that TNFRSF1A overexpression conferred carfilzomib resistance in MM cells and suppressed the expression of MHC genes and cell adhesion molecules. The suppression of MHC genes and cell adhesion molecules may impair the interaction between immune cells and cancer cells to impair antitumor immunity. Future studies are warranted to further investigate the signaling pathway underlying the regulatory role of TNFRSF1A in MM cells. [ABSTRACT FROM AUTHOR]

West African Mastomys rodents are the primary reservoir of the zoonotic Lassa virus (LASV). The virus causes haemorrhagic Lassa fever and considerable mortality in humans. To date, the role of Mastomys immunogenetics in resistance to, and persistence of, LASV infections is largely unknown. Here, we investigated the role of Major Histocompatibility Complex class I (MHC-I) on LASV infection status (i.e., active vs. cleared infection, determined via PCR and an immunofluorescence assay on IgG antibodies, respectively) in Mastomys natalensis and M. erythroleucus sampled within southwestern Nigeria. We identified more than 190 and 90 MHC-I alleles by Illumina high throughput-sequencing in M. natalensis and M. erythroleucus, respectively, with different MHC allele compositions and frequencies between LASV endemic and non-endemic sites. In M. natalensis, the MHC allele ManaMHC-I*006 was negatively associated with active infections (PCR-positive) and positively associated with cleared infections (IgG-positive) simultaneously, suggesting efficient immune responses that facilitate LASV clearance in animals carrying this allele. Contrarily, alleles ManaMHC-I*008 and ManaMHC-I*021 in M. natalensis, and MaerMHC-I*008 in M. erythroleucus, were positively associated with active infection, implying susceptibility. Alleles associated with susceptibility shared a glutamic acid at the positively selected codon 57, while ManaMHC-I*006 featured an arginine. There was no link between number of MHC alleles per Mastomys individual and LASV prevalence. Thus, specific alleles, but not MHC diversity per se, seem to mediate antibody responses to viremia. We conclude that co-evolution with LASV likely shaped the MHC-I diversity of the main LASV reservoirs in southwestern Nigeria, and that information on reservoir immunogenetics may hold insights into transmission dynamics and zoonotic spillover risks. Author summary: The Lassa virus is passed from rodents to humans, causing a disease that kills thousands of people every year in West Africa. To control spread, scientists are trying to understand why some rodents are more susceptible to the virus than others. One factor they are studying is the genetic makeup of the rodents' immune systems. They found that a specific allele of the Major Histocompatibility Complex (MHC I), called ManaMHC-I*006, was associated with resistance to and clearance of the virus, while other alleles were associated with susceptibility. They also found that the immunogenetic composition of rodents differed between areas where Lassa virus is endemic or non-endemic. These findings can help predict where the virus might emerge and can help researchers develop a vaccine to protect the rodents from getting the virus, which can ultimately help prevent the spread of the disease to humans. The authors emphasize the significance of adopting a One-Health approach in thinking about wildlife and human health. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T (MAIT) cells are an atypical subset of T lymphocytes, which have a highly conserved semi-constant αβ chain of T-cell receptor (TCR) and recognize microbe-derived vitamin B metabolites via major histocompatibility complex class I related-1 molecule (MR1). MAIT cells get activated mainly through unique TCR-dependent and TCR-independent pathways, and express multiple functional and phenotypic traits, including innate-like functionality, T helper (Th) 1 cell immunity, Th 17 cell immunity, and tissue homing. Given the functions, MAIT cells are extensively reported to play a key role in mucosal homeostasis and infectious diseases. In the current work, we review the basic characteristics of MAIT cells and their roles in mucosal homeostasis and development of respiratory infectious diseases as well as their potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Major Histocompatibility Complex (MHC) I and II and the ab T-cell antigen receptor (TCRab) govern fundamental traits of adaptive immunity. They form a membrane-borne ligand-receptor system weighing host proteome integrity to detect contamination by nonself proteins. MHC-I and -II exhibit the "MHC-fold", which is able to bind a large assortment of short peptides as proxies for self and nonself proteins. The ensuing varying surfaces are mandatory ligands for Ig-like TCRab highly mutable binding sites. Conserved molecular signatures guide TCRab ligand binding sites to focus on the MHC-fold (MHC-restriction) while leaving many opportunities for its most hypervariable determinants to contact the peptide. This riveting molecular strategy affords many options for binding energy compatible with specific recognition and signalling aimed to eradicated microbial pathogens and cancer cells. While the molecular foundations of ab Tcell adaptive immunity are largely understood, uncertainty persists on how peptide-MHC binding induces the TCRab signals that instruct cell-fate decisions. Solving this mystery is another milestone for understanding ab Tcells' self/nonself discrimination. Recent developments revealing the innermost links between TCRab structural dynamics and signalling modality should help dissipate this long-sought-after enigma. [ABSTRACT FROM AUTHOR]

Background: LATS1/2 are frequently mutated and down-regulated in endometrial cancer (EC), but the contributions of LATS1/2 in EC progression remains unclear. Impaired antigen presentation due to mutations or downregulation of the major histocompatibility complex class I (MHC-I) has been implicated in tumor immune evasion. Herein, we elucidate the oncogenic role that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I. Methods: The mutation and expression as well as the clinical significance of LATS1/2 in EC was assessed in the TCGA cohort and our sample cohort. CRISPR-Cas9 was used to construct knockout cell lines of LATS1/2 in EC. Differentially expressed genes were analyzed by RNA-seq. The interaction between LATS1/2 and STAT1 was verified using co-immunoprecipitation and GST pull-down assays. Mass spectrometry, in vitro kinase assays, ChIP-qPCR, flow cytometry, immunohistochemistry, immunofluorescence and confocal microscopy were performed to investigate the regulation of LATS1/2 on MHC-I through interaction with and phosphorylate STAT1. The killing effect of activated PBMCs on EC cells were used to monitor anti-tumor activity. Results: Here, we demonstrate that LATS1/2 are frequently mutated and down-regulated in EC. Moreover, LATS1/2 loss was found to be associated with a significant down-regulation of MHC-I, independently of the Hippo-YAP pathway. Instead, LATS1/2 were found to directly interact with and phosphorylate STAT1 at Ser727, a crucial transcription factor for MHC-I upregulation in response to interferon-gamma (IFN-γ) signaling, to promote STAT1 accumulating and moving into the nucleus to enhance the transcriptional activation of IRF1/NLRC5 on MHC-I. Additionally, the loss of LATS1/2 was observed to confer increased resistance of EC cells to immune cell-mediated killing and this resistance could be reversed by over-expression of MHC-I. Conclusion: Our findings indicate that dysregulation of LATS1/2 in EC leads to immune evasion through the down-regulation of MHC-I, leading to the suppression of infiltrating activated CD8 + T cells and highlight the importance of LATS1/2 in IFN-γ signaling-mediated tumor immune response, suggesting that LATS1/2 is a promising target for immune checkpoint blockade therapy in EC. [ABSTRACT FROM AUTHOR]

The exceptional polymorphism observed within genes of the major histocompatibility complex (MHC), a core component of the vertebrate immune system, has long fascinated biologists. The highly polymorphic classical MHC class-I (MHC-I) genes are maintained by pathogen-mediated balancing selection (PMBS), as shown by many sites subject to positive selection, while the more monomorphic non-classical MHC-I genes show signatures of purifying selection. In line with PMBS, at any point in time, rare classical MHC alleles are more likely than common classical MHC alleles to confer a selective advantage in host–pathogen interactions. Combining genomic and expression data from the blood of wild house sparrows Passer domesticus, we found that only rare classical MHC-I alleles were highly expressed, while common classical MHC-I alleles were lowly expressed or not expressed. Moreover, highly expressed rare classical MHC-I alleles had more positively selected sites, indicating exposure to stronger PMBS, compared with lowly expressed classical alleles. As predicted, the level of expression was unrelated to allele frequency in the monomorphic non-classical MHC-I alleles. Going beyond previous studies, we offer a fine-scale view of selection on classical MHC-I genes in a wild population by revealing differences in the strength of PMBS according to allele frequency and expression level. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) show promise as second‐line treatment for advanced bladder cancer (BLCA); however, their responsiveness is limited by the immune evasion mechanisms in tumor cells. This study conduct a Cox regression analysis to screen mRNA‐binding proteins and reveals an association between Ras GTPase‐activating protein‐binding protein 1 (G3BP1) and diminished effectiveness of ICI therapy in patients with advanced BLCA. Subsequent investigation demonstrates that G3BP1 enhances immune evasion in BLCA cells by downregulating major histocompatibility complex class I (MHC‐I) through phosphoinositide 3‐kinase (PI3K)/Akt signaling activation. Mechanistically, G3BP1 interacts with splicing factor synergistic lethal with U5 snRNA 7 (SLU7) to form a complex with poly(A)‐binding protein cytoplasmic 1 and eukaryotic translation initiation factor 4 gamma 1. This complex stabilizes the closed‐loop structure of the mRNAs of class IA PI3Ks and consequently facilitates their translation and stabilization, thereby activating PI3K/Akt signaling to downregulate MHC‐I. Consistently, targeting G3BP1 with epigallocatechin gallate (EGCG) impedes immune evasion and sensitizes BLCA cells to anti‐programmed cell death (PD)‐1 antibodies in mice. Thus, G3BP1 and SLU7 collaboratively contribute to immune evasion in BLCA, indicating that EGCG is a precision therapeutic agent to enhance the effectiveness of anti‐PD‐1 therapy. [ABSTRACT FROM AUTHOR]

Mechanical force is critical for the interaction between an αβ T cell receptor (TCR) and a peptide-bound major histocompatibility complex (pMHC) molecule to initiate productive T-cell activation. However, the underlying mechanism remains unclear. We use all-atom molecular dynamics simulations to examine the A6 TCR bound to HLA-A* 02:01 presenting agonist or antagonist peptides under different extensions to simulate the effects of applied load on the complex, elucidating their divergent biological responses. We found that TCR α and β chains move asymmetrically, which impacts the interface with pMHC, in particular the peptide-sensing CDR3 loops. For the wild-type agonist, the complex stabilizes in a load-dependent manner while antagonists destabilize it. Simulations of the Cβ FG-loop deletion, which reduces the catch bond response, and simulations with in silico mutant peptides further support the observed behaviors. The present results highlight the combined role of interdomain motion, fluctuating forces, and interfacial contacts in determining the mechanical response and fine peptide discrimination by a TCR, thereby resolving the conundrum of nearly identical crystal structures of TCRαβ-pMHC agonist and antagonist complexes. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex (MHC) can recognize and bind to external peptides to generate effective immune responses by presenting the peptides to T cells. Therefore, understanding the binding modes of peptide–MHC complexes (pMHC) and predicting the binding affinity of pMHCs play a crucial role in the rational design of peptide vaccines. In this study, we employed molecular dynamics (MD) simulations and free energy calculations with an Alanine Scanning with Generalized Born and Interaction Entropy (ASGBIE) method to investigate the protein–peptide interaction between HLA-A*02:01 and the G9209 peptide derived from the melanoma antigen gp100. The energy contribution of individual residue was calculated using alanine scanning, and hotspots on both the MHC and the peptides were identified. Our study shows that the pMHC binding is dominated by the van der Waals interactions. Furthermore, we optimized the ASGBIE method, achieving a Pearson correlation coefficient of 0.91 between predicted and experimental binding affinity for mutated antigens. This represents a significant improvement over the conventional MM/GBSA method, which yields a Pearson correlation coefficient of 0.22. The computational protocol developed in this study can be applied to the computational screening of antigens for the MHC1 as well as other protein–peptide binding systems. [ABSTRACT FROM AUTHOR]

A feature of the SARS-CoV-2 Omicron subvariants BF.5 and BF.7 that recently circulated mainly in China and Japan was the high prevalence of the ORF7a: H47Y mutation, in which the 47th residue of ORF7a has been mutated from a histidine (H) to a tyrosine (Y). Here, we evaluated the effect of this mutation on the three main functions ascribed to the SARS-CoV-2 ORF7a protein. Our findings show that H47Y mutation impairs the ability of SARS-CoV-2 ORF7a to antagonize the type I interferon (IFN-I) response and to downregulate major histocompatibility complex I (MHC-I) cell surface levels, but had no effect in its anti-SERINC5 function. Overall, our results suggest that the H47Y mutation of ORF7a affects important functions of this protein, resulting in changes in virus pathogenesis. [ABSTRACT FROM AUTHOR]

The Human leukocyte antigen (HLA) molecules are central to immune response and have associations with the phenotypes of various diseases and induced drug toxicity. Further, the role of HLA molecules in presenting antigens significantly affects the transplantation outcome. The objective of this study was to examine the extent of the diversity of HLA alleles in the population of the United Arab Emirates (UAE) using Next-Generation Sequencing methodologies and encompassing a larger cohort of individuals. A cohort of 570 unrelated healthy citizens of the UAE volunteered to provide samples for Whole Genome Sequencing and Whole Exome Sequencing. The definition of the HLA alleles was achieved through the application of the bioinformatics tools, HLA-LA and xHLA. Subsequently, the findings from this study were compared with other local and international datasets. A broad range of HLA alleles in the UAE population, of which some were previously unreported, was identified. A comparison with other populations confirmed the current population's unique intertwined genetic heritage while highlighting similarities with populations from the Middle East region. Some disease-associated HLA alleles were detected at a frequency of > 5%, such as HLA-B*51:01, HLA-DRB1*03:01, HLA-DRB1*15:01, and HLA-DQB1*02:01. The increase in allele homozygosity, especially for HLA class I genes, was identified in samples with a higher level of genome-wide homozygosity. This highlights a possible effect of consanguinity on the HLA homozygosity. The HLA allele distribution in the UAE population showcases a unique profile, underscoring the need for tailored databases for traditional activities such as unrelated transplant matching and for newer initiatives in precision medicine based on specific populations. This research is part of a concerted effort to improve the knowledge base, particularly in the fields of transplant medicine and investigating disease associations as well as in understanding human migration patterns within the Arabian Peninsula and surrounding regions. [ABSTRACT FROM AUTHOR]

Chemotherapy is often a life-saving treatment, but the development of intractable pain caused by chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting toxicity that restricts cancer survival rates. Recent reports demonstrate that paclitaxel (PTX) robustly increases anti-inflammatory CD4+ T cells in the dorsal root ganglion (DRG), and that T cells and anti-inflammatory cytokines are protective against CIPN. However, the mechanism by which CD4+ T cells are activated, and the extent cytokines released by CD4+ T cells target DRG neurons are unknown. Here, we are the first to detect major histocompatibility complex II (MHCII) protein in mouse DRG neurons and to find CD4+ T cells breaching the satellite glial cell barrier to be in close proximity to neurons, together suggesting CD4+ T cell activation and targeted cytokine release. MHCII protein is primarily expressed in small nociceptive neurons in male and female mouse DRG but increased after PTX in small nociceptive neurons in only female DRG. Reducing one copy of MHCII in small nociceptive neurons decreased anti-inflammatory IL-10 and IL-4 producing CD4+ T cells in naïve male DRG and increased their hypersensitivity to cold. Administration of PTX to male and female mice that lacked one copy of MHCII in nociceptive neurons decreased anti-inflammatory CD4+ T cells in the DRG and increased the severity of PTX-induced cold hypersensitivity. Collectively, our results demonstrate expression of MHCII protein in mouse DRG neurons, which modulates cytokine producing CD4+ T cells in the DRG and attenuates cold hypersensitivity during homeostasis and after PTX treatment. [ABSTRACT FROM AUTHOR]

Introduction: The Ovar-DRB1 gene, a crucial element of the Major Histocompatibility Complex (MHC) Class II region, initiates adaptive immunity by presenting antigens to T-cells. Genetic diversity in sheep, particularly in MHC Class II genes like Ovar-DRB1, directly influences the specturm of presented antigens impacting immune responses and disease susceptability. Understanding the allelic diversity of Ovar-DRB1 gene in Sudan Desert Sheep (SDS) is essential for uncovering the genetic basis of immune responses and disease resistance, given the the breeds significance in Sudan's unique environment. Methods: Utilizing Targeted Next-Generation Sequencing (NGS) we explore allelic diversity in Ovar-DRB1 gene within SDS. Successfully ampliying and and sequencing the second exon of this gene in 288 SDS samples representing six breeds provided a comprehensive allelic profile, enabling a detalied examination of the gene's genetic makeup. Results: We identifed forty-six alleles, including four previously unreported, enrichness the genetic diversity of SDS breeds. These alleles exhibiting non-uniform distribution, varying frequencies across breeds, indicating a breed-specific genetic landscape. Certain alleles, known and novel, show higher frequencies in specific populations, suggesting potential associations with adaptive immune responses. Identifying these alleles sets the stage for investigating their functional roles and implications for disease resistance. Genetic differentiation among SDS breeds, as indicated by FST values and clustering analyses, highlights a unique genetic makeup shaped by geographic and historical factors. These differentiation patterns among SDS breeds have broader implications for breed conservation and targeted breeding to enhance disease resistance in specific populations. Conclusion: This study unveils Ovar-DRB1 gene allelic diversity in SDS breeds through targeted NGS and genetic analyses, revealing new alleles that underscore the breeds' unique genetic profile. Insights into the genetic factors governing immune responses and disease resistance emerge, promising for optimization of breeding strategies for enhanced livestock health in Sudan's unique environment. [ABSTRACT FROM AUTHOR]

Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer. [ABSTRACT FROM AUTHOR]

Background: Sepsis-induced acute lung injury (ALI) poses a significant threat to human health. Endothelial cells, especially pulmonary capillaries, are the primary barriers against sepsis in the lungs. Therefore, investigating endothelial cell function is essential to understand the pathophysiological processes of sepsisinduced ALI. Methods: We downloaded single-cell RNA-seq expression data from GEO with accession number GSE207651. The mice underwent cecal ligation and puncture (CLP) surgery, and lung tissue samples were collected at 0, 24, and 48 h. The cells were annotated using the CellMarker database and FindAllMarkers functions. GO enrichment analyses were performed using the Metascape software. Gene set enrichment Analysis (GSEA) and variation Analysis (GSVA) were performed to identify differential signaling pathways. Differential expression genes were collected with the "FindMarkers" function. The R package AUCell was used to score individual cells for pathway activities. The Cellchat package was used to explore intracellular communication. Results: Granulocytes increased significantly as the duration of endotoxemia increased. However, the number of T cells, NK cells, and B cells declined. Pulmonary capillary cells were grouped into three sub-clusters. Capillary-3 cells were enriched in the sham group, but declined sharply in the CLP.24 group. Capillary-1 cells peaked in the CLP.24 group, while Capillary-2 cells were enriched in the CLP.48 group. Furthermore, we found that Cd74+ Capillary-3 cells mainly participated in immune interactions. Plat+ Capillary-1 and Clec1a+ Capillary-2 are involved in various physiological processes. Regarding cell-cell interactions, Plat+ Capillary-1 plays the most critical role in granulocyte adherence to capillaries during ALI. Cd74+ Capillary cells expressing high levels of major histocompatibility complex (MHC) and mainly interacted with Cd8a+ T cells in the sham group. Conclusion: Plat+ capillaries are involved in the innate immune response through their interaction with neutrophils via ICAM-1 adhesion during endotoxemia, while Cd74+ capillaries epxressed high level of MHC proteins play a role in adaptive immune response through their interaction with T cells. However, it remains unclear whether the function of Cd74+ capillaries leans towards immunity or tolerance, and further studies are needed to confirm this. [ABSTRACT FROM AUTHOR]

Naive T cells experience tonic T cell receptor (TCR) signaling in response to self-antigens presented by major histocompatibility complex (MHC) in secondary lymphoid organs. We investigated how relatively weak or strong tonic TCR signals influence naive CD8+ T cell responses to stimulation with foreign antigens. The heterogeneous expression of Nur77-GFP, a transgenic reporter of tonic TCR signaling, in naive CD8+ T cells suggests variable intensities or durations of tonic TCR signaling. Although the expression of genes associated with acutely stimulated T cells was increased in Nur77-GFPHI cells, these cells were hyporesponsive to agonist TCR stimulation compared with Nur77-GFPLO cells. This hyporesponsiveness manifested as diminished activation marker expression and decreased secretion of IFN-γ and IL-2. The protein abundance of the ubiquitin ligase Cbl-b, a negative regulator of TCR signaling, was greater in Nur77-GFPHI cells than in Nur77-GFPLO cells, and Cbl-b deficiency partially restored the responsiveness of Nur77-GFPHI cells. Our data suggest that the cumulative effects of previously experienced tonic TCR signaling recalibrate naive CD8+ T cell responsiveness. These changes include gene expression changes and negative regulation partially dependent on Cbl-b. This cell-intrinsic negative feedback loop may enable the immune system to restrain naive CD8+ T cells with higher self-reactivity. Editor's summary: Naive T cells in the periphery constitutively experience varying amounts of tonic T cell receptor (TCR) signaling. Eggert et al. determined how this baseline TCR signaling affects the responsiveness of naive CD8+ T cells to antigens. High amounts of tonic TCR signaling resulted in hyporesponsiveness to agonist TCR stimulation, which was associated with increased abundance of the ubiquitin ligase Cbl-b, an inhibitor of TCR signaling. Deficiency in Cbl-b partially restored responsiveness. These results uncover a negative feedback loop that restrains the responsiveness of naive T cells in the face of strong tonic TCR signaling. —Wei Wong [ABSTRACT FROM AUTHOR]

Background: The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A virus (IAV), harbors almost all subtypes of IAVs and resists to many IAVs which cause extreme virulence in chicken and human. However, the response of duck's adaptive immune system to IAV infection is poorly characterized due to lack of a detailed gene map of the major histocompatibility complex (MHC). Results: We herein reported a chromosome-scale Beijing duck assembly by integrating Nanopore, Bionano, and Hi-C data. This new reference genome SKLA1.0 covers 40 chromosomes, improves the contig N50 of the previous duck assembly with highest contiguity (ZJU1.0) of more than a 5.79-fold, surpasses the chicken and zebra finch references in sequence contiguity and contains a complete genomic map of the MHC. Our 3D MHC genomic map demonstrated that gene family arrangement in this region was primordial; however, families such as AnplMHCI, AnplMHCIIβ, AnplDMB, NKRL (NK cell receptor-like genes) and BTN underwent gene expansion events making this area complex. These gene families are distributed in two TADs and genes sharing the same TAD may work in a co-regulated model. Conclusions: These observations supported the hypothesis that duck's adaptive immunity had been optimized with expanded and diversified key immune genes which might help duck to combat influenza virus. This work provided a high-quality Beijing duck genome for biological research and shed light on new strategies for AIV control. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockades have been prized in circumventing and ablating the impediments posed by immunosuppressive receptors, reaching an exciting juncture to be an innovator in anticancer therapy beyond traditional therapeutics. Thus far, approved immune checkpoint blockades have principally targeted PD-1/PD-L1 and CTLA-4 with exciting success in a plethora of tumors and yet are still trapped in dilemmas of limited response rates and adverse effects. Hence, unveiling new immunotherapeutic targets has aroused immense scientific interest in the hope of expanding the clinical application of immune checkpoint blockades to scale new heights. Human leukocyte antigen-G (HLA-G), a non-classical major histocompatibility complex (MHC) class I molecule, is enriched on various malignant cells and is involved in the hindrance of immune effector cells and the facilitation of immunosuppressive cells. HLA-G stands out as a crucial next-generation immune checkpoint showing great promise for the benefit of cancer patients. Here, we provide an overview of the current understanding of the expression pattern and immunological functions of HLA-G, as well as its interaction with well-characterized immune checkpoints. Since HLA-G can be shed from the cell surface or released by various cells as free soluble HLA-G (sHLA-G) or as part of extracellular vesicles (EVs), namely HLA-G-bearing EVs (HLA-GEV), we discuss the potential of sHLA-G and HLA-GEV as predictive biomarkers. This review also addresses the advancement of HLA-G-based therapies in preclinical and clinical settings, with a focus on their clinical application in cancer. [ABSTRACT FROM AUTHOR]

Mate choice is hypothesized to play an important role in maintaining high diversity at major histocompatibility complex (MHC) genes in vertebrates. Many studies have revealed that females across taxa prefer the scent of males with MHC genotypes different to their own. In this study we tested the "opposites‐attract" hypothesis in two species of darter with known differences in female criteria used in mate choice: in the fantail darters (a paternal‐care species), females prefer males with visual traits related to nest guarding and egg tending, while in rainbow darters (not a paternal‐care species) female mate choice criteria are unknown. In dichotomous mate‐choice trials, we presented females of both species with the scents of conspecific males with MHC class IIb genotypes that were either similar or dissimilar to that of the focal female. We evaluated the proportion of time each female spent with each male and calculated the average strength of female preference for both species. Female fantail darters demonstrated a preference for the scent of males with similar (rather than dissimilar) MHC genotypes, but this result was not statistically significant. Rainbow darter females showed no preference for the scent of males with similar or dissimilar MHC genotypes. Our results do not support the "opposites‐attract" hypothesis in darters. [ABSTRACT FROM AUTHOR]

The selective pressure from pathogens on individuals can have direct consequences on reproduction. Genes from the major histocompatibility complex (MHC) are central to the vertebrate adaptive immune system and pathogen resistance. In species with biparental care, each sex has distinct reproductive roles and levels of investment, and due to a trade‐off with immunity, one can expect different selective regimes acting upon the MHC of each parent. Here, we addressed whether couples combine each other's variation at MHC loci to increase their breeding success. Specifically, we used a 23‐year dataset from a barn owl population (Tyto alba) to understand how MHC class Iα and IIβ functional divergence and supertypes of each parent were associated with clutch size and fledging success. We did not detect associations between MHC diversity and supertypes with the clutch size or with the fledging success. In addition, to understand the relative contribution from the MHC of the genetic parents and the social parents, we analyzed the fledging success using only a cross‐fostered dataset. We found several associations of weak‐to‐moderate effect sizes between the father's MHC and fledging success: (i) lower MHC‐Iα divergence in the genetic father increases fledging success, which might improve paternal care during incubation, and (ii) one and two MHC‐IIβ DAB2 supertypes in the social father decrease and increase, respectively, fledging success, which may affect the paternal care after hatching. Furthermore, fledging success increased when both parents did not carry MHC‐IIβ DAB1 supertype 2, which could suggest conditional effects of this supertype. Although our study relied on a substantial dataset, we showed that the associations between MHC diversity and reproductive success remain scarce and of complex interpretation in the barn owl. Moreover, our results highlighted the need to incorporate more than one proxy of reproductive success and several MHC classes to capture more complex associations. [ABSTRACT FROM AUTHOR]

• The MR1/MAIT cell innate immune axis is understudied in CNS disorders. • Pathology in several CNS diseases involves MR1 and/or MAIT cells. • Elevated of MR1 expression in glioblastoma predicts a poor outcome for patients. • MAIT cell numbers are elevated in multiple sclerosis. • Not all animal models of immune-mediated CNS disorders truly reflect human disease. Mucosal-associated invariant T (MAIT) cells are a subpopulation of innate-like T cells that can be found throughout the body, predominantly in mucosal sites, the lungs and in the peripheral blood. MAIT cells recognize microbial-derived vitamin B (e.g., riboflavin) metabolite antigens that are presented by the major histocompatibility complex class I-like protein, MR1, found on a variety of cell types in the periphery and the CNS. Since their original discovery, MAIT cells have been studied predominantly in their roles in diseases in the periphery; however, it was not until the early 2000s that these cells were first examined for their contributions to disorders of the CNS, with the bulk of the work being done within the past few years. Currently, the MR1/MAIT cell axis has been investigated in only a few neurological diseases including, multiple sclerosis and experimental autoimmune encephalomyelitis, brain cancer/tumors, ischemia, cerebral palsy, general aging and, most recently, Alzheimer's disease. Each of these diseases demonstrates a role for this under-studied innate immune axis in its neuropathology. Together, they highlight the importance of studying the MR1/MAIT cell axis in CNS disorders. Here, we review the contributions of the MR1/MAIT cell axis in the progression or remission of these neurological diseases. This work has shed some light in terms of potentially exploiting the MR1/MAIT cell axis in novel therapeutic applications. [ABSTRACT FROM AUTHOR]

The breadth of pathogens to which T cells can respond is determined by the T cell receptors (TCRs) present in an individual's repertoire. Although more than 90% of the sequence diversity among TCRs is generated by terminal deoxynucleotidyl transferase (TdT)-mediated N-nucleotide addition during V(D)J recombination, the benefit of TdT-altered TCRs remains unclear. Here, we computationally and experimentally investigated whether TCRs with higher N-nucleotide diversity via TdT make distinct contributions to acute or chronic pathogen control specifically through the inclusion of TCRs with lower antigen binding strengths (i.e., lower reactivity to peptide-major histocompatibility complex (pMHC)). When T cells with high pMHC reactivity have a greater propensity to become functionally exhausted than those of low pMHC reactivity, our computational model predicts a shift toward T cells with low pMHC reactivity over time during chronic, but not acute, infections. This TCR-affinity shift is critical, as the elimination of T cells with lower pMHC reactivity in silico substantially increased the time to clear a chronic infection, while acute infection control remained largely unchanged. Corroborating an affinity-centric benefit for TCR diversification via TdT, we found evidence that TdT-deficient TCR repertoires possess fewer T cells with weaker pMHC binding strengths in vivo and showed that TdT-deficient mice infected with a chronic, but not an acute, viral pathogen led to protracted viral clearance. In contrast, in the case of a chronic fungal pathogen where T cells fail to clear the infection, both our computational model and experimental data showed that TdT-diversified TCR repertoires conferred no additional protection to the hosts. Taken together, our in silico and in vivo data suggest that TdT-mediated TCR diversity is of particular benefit for the eventual resolution of prolonged pathogen replication through the inclusion of TCRs with lower foreign antigen binding strengths. Although more than 90% of the sequence diversity among T cell receptors (TCRs) is generated by terminal deoxynucleotidyl transferase (TdT)-mediated nucleotide addition, the benefit of TdT-altered TCRs remains unclear. This study shows that low-affinity T cells generated by TdT are important for curtailing chronic pathogen replication. [ABSTRACT FROM AUTHOR]

The immunogenome is the part of the genome that underlies immune mechanisms and evolves under various selective pressures. Two complex regions of the immunogenome, major histocompatibility complex (MHC) and natural killer cell receptor (NKR) genes, play an important role in the response to selective pressures of pathogens. Their importance is expressed by their genetic polymorphism at the molecular level, and their diversity associated with different types of diseases at the population level. Findings of associations between specific combinations of MHC/NKR haplotypes with different diseases in model species suggest that these gene complexes did not evolve independently. No such associations have been described in horses so far. The aim of the study was to detect associations between MHC and NKR gene/microsatellite haplotypes in three horse breed groups (Camargue, African, and Romanian) by statistical methods; chi‐square test, Fisher's exact test, Pearson's goodness‐of‐fit test and logistic regression. Associations were detected for both MHC/NKR genes and microsatellites; the most significant associations were found between the most variable KLRA3 gene and the EQCA‐1 or EQCA‐2 genes. This finding supports the assumption that the KLRA3 is an important receptor for MHC I and that interactions of these molecules play important roles in the horse immunity and reproduction. Despite some limitations of the study such as low numbers of horses or lack of knowledge of the selected genes functions, the results were consistent across different statistical methods and remained significant even after overconservative Bonferroni corrections. We therefore consider them biologically plausible. [ABSTRACT FROM AUTHOR]

Domestic sheep (Ovis aries) have been an important component of livestock agricultural production for thousands of years. Preserving genetic diversity within livestock populations maintains a capacity to respond to changing environments and rapidly evolving pathogens. MHC genetic diversity can influence immune functionality at individual and population levels. Here, we focus on defining functional MHC class I haplotype diversity in a large cohort of Scottish Blackface sheep pre‐selected for high levels of MHC class II DRB1 diversity. Using high‐throughput amplicon sequencing with three independent sets of barcoded primers we identified 134 MHC class I transcripts within 38 haplotypes. Haplotypes were identified with between two and six MHC class I genes, plus variable numbers of conserved sequences with very low read frequencies. One or two highly transcribed transcripts dominate each haplotype indicative of two highly polymorphic, classical MHC class I genes. Additional clusters of medium, low, and very low expressed transcripts are described, indicative of lower transcribed classical, non‐classical and genes whose function remains to be determined. [ABSTRACT FROM AUTHOR]

Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima's D , HKA, D ng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was explored, as well, using: (i) SNP genotyping and exome data, (ii) targeted high-resolution HLA genotyping (IHIW), and (iii) whole-genome long-read sequencing data (Pangenome). In the analysis of SNP genotyping and exome data, we identified known targets and 38 new selection signatures in genes not previously linked to balancing selection. To further investigate the impact of sequencing quality on detection of balancing selection, a detailed investigation of the MHC was performed with high-resolution HLA typing data. Higher quality sequencing revealed the HLA-DQ genes consistently demonstrated strong selection signatures otherwise not observed from the sparser SNP array and exome data. The HLA-DQ selection signature was also replicated in the Pangenome samples using considerably less samples but, with high-quality long-read sequence data. The improved statistical method, coupled with higher quality sequencing, leads to more consistent identification of selection and enhanced localization of variants under selection, particularly in complex regions. [ABSTRACT FROM AUTHOR]

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium. This strategy allowed us to avoid off-target effects on iron homeostasis and class I-like molecules, which are known to perturb Plasmodium infection. This is the first endothelial-specific ablation of individual class-I molecules enabling us to interrogate these molecular interactions. In these studies, we interrogated human and mouse transcriptomics data to compare antigen presentation capacity during cerebral malaria. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM), we observed that H-2Kb and H-2Db class I molecules regulate distinct patterns of disease onset, CD8 T-cell infiltration, targeted cell death and regional blood–brain barrier disruption. Strikingly, ablation of either molecule from brain endothelial cells resulted in reduced CD8 T-cell activation, attenuated T-cell interaction with brain vasculature, lessened targeted cell death, preserved blood–brain barrier integrity and prevention of ECM and the death of the animal. We were able to show that these events were brain-specific through the use of parabiosis and created the novel technique of dual small animal MRI to simultaneously scan conjoined parabionts during infection. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium differentially regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria. [ABSTRACT FROM AUTHOR]

The study investigated the prognostic and immune predictive potential of major histocompatibility complex class I (MHC-I) in lung adenocarcinoma (LUAD). With The Cancer Genome Atlas (TCGA)-LUAD and Gene Expression Omnibus datasets (GSE26939, GSE72094) as the training and validation sets, respectively, we used Cox regression analysis to construct a prognostic model, and verified independence of riskscore. The predictive capacity of the model was assessed in both sets using the receiver operating characteristic curve and Kaplan-Meier survival curves. Immune analysis was performed by using ssGSEA. Additionally, immune checkpoint blockade therapy was assessed by using immunophenoscore, Tumor Immune Dysfunction and Exclusion score. Based on the cMAP database, effective small molecule compounds were predicted. A prognostic model was established based on 8 MHC-I-related genes, and the predictive capacity of the model was accurate. Immune analysis results revealed that patients classified as high-risk had lower levels of immune cell infiltration and impaired immune function. The low-risk group possessed a better response to immune checkpoint blockade therapy. Theobromine and pravastatin were identified as having great potential in improving the prognosis of LUAD. Overall, the study revealed MHC-I-related molecular prognostic biomarkers as robust indicators for LUAD prognosis and immune therapy response. [ABSTRACT FROM AUTHOR]

In natural populations, hybridization is known to occur between a wide range of species. However, its evolutionary significance is less clear. Genes involved in fighting pathogens are considered excellent candidates for studying adaptive introgression, although both introgression and balancing selection can generate similar patterns of diversity and differentiation. Here, we compared DQA and DQB MHC class II and microsatellite allelic diversity of sympatric and parapatric mountain (Lepus timidus) and brown hare (L. europaeus) populations from Switzerland. We detected higher genetic diversity in brown hares compared to mountain hares at both MHC and microsatellite loci. We consider the observed patterns of microsatellite diversity both for L. europaeus and L. timidus as result of stochastic demographic processes while the pattern of MHC polymorphism of the studied hare populations can be explained by pathogen-driven selection. Rare bidirectional gene flow between both hare species seems to occur specifically for MHC alleles. However, the high number of shared alleles showing similar high frequency in both species suggests that reciprocally exchanged MHC alleles are being maintained via balancing selection. Adaptation to similar pathogen communities can also lead to parallel selection of MHC alleles. Positive selection, recombination and mutations have played different roles in shaping the patterns of MHC allelic diversity in and differentiation between both species. Results for the latter evolutionary forces do not show a better matching between the sympatric populations compared to the parapatric ones, suggesting a minor role of introgression for the observed evolutionary patterns of the studied hare species. [ABSTRACT FROM AUTHOR]

• Pre-existing immunity against recent SARS-CoV-2 strains in Vietnam was determined. • Pre-COVID-19 samples neutralize Wuhan and Alpha strains but not newer variants. • Limited cellular immunity to SARS-CoV-2 suggests a lack of cross-immunity among newer variants of concern. • Pre-COVID-19 immunity may influence low transmission in the early phase of a pandemic. SARS-CoV-2 transmission and epidemic potential is related to the population's immunity levels. As such, assessing different regions' preexisting immune responses to SARS-CoV-2 is important to understand the transmission potential of emerging SARS-CoV-2 variants. In 975 serum samples from Vietnam (2014 to 2019), anti-SARS-CoV-2 Immunoglobulin G levels were determined by enzyme-linked immunosorbent assay. Plaque reduction neutralization test (PRNT) was performed using Wuhan strain and variants of concern (VOCs). Cross-reactivity was confirmed by analyzing B-cell receptor (BCR) repertoire sequences and identifying BCR repertoire sequences-derived T-cell epitopes. Overall, 20.9% (n = 76/364) and 9.2% (n = 7) demonstrated SARS-CoV-2 neutralizing activity (PRNT 50) against the Wuhan and Alpha strain, respectively. Neutralizing activity against Beta, Gamma, and Delta strains was absent (PRNT 50 <5) in all samples. Cross-reactive epitopes against SARS-CoV-2 and other coronavirus spike proteins were detected in the N-terminal domain, S2, and receptor-binding domain regions. Following BCR and major histocompatibility complex analysis, T-cell receptor-recognized epitope motif (TREM) among pathogenic coronaviruses and coronaviruses spike proteins were the top TREM peptide, suggesting that pre-existing immunity against SARS-CoV-2 in Vietnam was due to exposure to common cold coronaviruses. With limited immunity against emerging VOCs, further monitoring, and control of the epidemic, along with COVID-19 vaccine programs against VOCs, are necessary. [ABSTRACT FROM AUTHOR]

Monocyte dysfunction is critical to sepsis-induced immunosuppression. Programmed death ligand-1 (PD-L1) has shown a close relationship with inflammatory disorder among animal models and patients. We aimed to investigate the potential beneficial immunologic mechanisms of anti-PD-L1 on monocyte dysfunction of mice with sepsis. Firstly, we assessed the potential association between PD-L1 expression on monocyte subsets and sepsis severity as well as 28-day mortality. In this study, 52 septic patients, 28 septic shock patients, and 40 healthy controls were enrolled and their peripheral whole blood was examined by flow cytometry. Then, cecal ligation and puncture (CLP) were performed for establishing the mouse sepsis model. Subsequently, effects of anti-PD-L1 antibody on monocyte subset, major histocompatibility complex II (MHC II) expression, cytokine production, and survival were investigated. PD-L1 expression on the classical monocytes (CD14 + + CD16 −) was significantly upregulated among septic shock patients and the 28-day death group than non-septic shock group and 28-day survival group (P < 0.05). Compared to septic mice, anti-PD-L1-treated mice had significantly elevated percentages of major histocompatibility complex (MHC) II on peripheral Ly6chi monocyte at 24 h after CLP. Our results showed that the anti-PD-L1 antibody markedly decreased the level of serum inflammatory cytokines interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-10 in sepsis mice at 24 h, 48 h, and 72 h, respectively (P < 0.05). The survival rate of CLP mice was significantly improved by anti-PD-L1 antibody treatment. Classical monocytes with high expression of PD-L1 were thought to be connected with sepsis progression. The PD-L1 blockade protects from sepsis, at least partially by inhibiting the reversal of monocyte dysfunction. [ABSTRACT FROM AUTHOR]

To assess the efficacy and tolerance of hydroxychloroquine in sarcoidosis-associated uveitis Retrospective study on all patients with sarcoidosis-associated uveitis who were treated with hydroxychloroquine between 2003 and 2019 in a French university hospital. Twenty-seven patients with sarcoidosis-associated uveitis received hydroxychloroquine. The mean duration of treatment was 20.0 ± 10.9 months. At the end of the follow-up, hydroxychloroquine success was achieved in 15 (55.6%) patients. Four of them were also on oral corticosteroids, with a prednisone dose ≤5 mg/day. Under treatment, the median prednisone dose decreased from 20.0 (interquartile range (IQR), 7–25) to 5.0 (IQR, 3–6.5) mg/day (p =.02). The incidence rate of flare decreased from 204.6 to 63.8 per 100 person-years (p =.02). Hydroxychloroquine was discontinued in 12 (44.4%) patients during follow-up, including 8 (29.6%) for ineffectiveness, and three who experienced side effects. Hydroxychloroquine appears as an interesting option in sarcoidosis-associated uveitis. Abbreviations: AZA: Azathioprine; BAL: Bronchoalveolar Lavage; BCVA: Best-Corrected Visual Acuity; ENT: Ears, Nose and Throat; HCQ: Hydroxychloroquine; IOP: Intra-Ocular Pressure; IQR: interquartile range; MHC: Major Histocompatibility Complex; MMF: Mycophenolate Mofetil; MTX: Methotrexate; PMSI: Programme de Médicalisation du Système d'Information; SAU: Sarcoidosis-Associated Uveitis; SD: Standard Deviation; SUN: Standard Uveitis Nomenclature [ABSTRACT FROM AUTHOR]

The prediction of major histocompatibility complex (MHC)-peptide binding affinity is an important branch in immune bioinformatics, especially helpful in accelerating the design of disease vaccines and immunity therapy. Although deep learning-based solutions have yielded promising results on MHC-II molecules in recent years, these methods ignored structure knowledge from each peptide when employing the deep neural network models. Each peptide sequence has its specific combination order, so it is worth considering adding the structural information of the peptide sequence to the deep model training. In this work, we use positional encoding to represent the structural information of peptide sequences and validly combine the positional encoding with existing models by different strategies. Experiments on three datasets show that the introduction of position-coding information can further improve the performance built upon the existing model. The idea of introducing positional encoding to this field can provide important reference significance for the optimization of the deep network structure in the future. [ABSTRACT FROM AUTHOR]

Bias in neural network model training datasets has been observed to decrease prediction accuracy for groups underrepresented in training data. Thus, investigating the composition of training datasets used in machine learning models with healthcare applications is vital to ensure equity. Two such machine learning models are NetMHCpan-4.1 and NetMHCIIpan-4.0, used to predict antigen binding scores to major histocompatibility complex class I and II molecules, respectively. As antigen presentation is a critical step in mounting the adaptive immune response, previous work has used these or similar predictions models in a broad array of applications, from explaining asymptomatic viral infection to cancer neoantigen prediction. However, these models have also been shown to be biased toward hydrophobic peptides, suggesting the network could also contain other sources of bias. Here, we report the composition of the networks' training datasets are heavily biased toward European Caucasian individuals and against Asian and Pacific Islander individuals. We test the ability of NetMHCpan-4.1 and NetMHCpan-4.0 to distinguish true binders from randomly generated peptides on alleles not included in the training datasets. Unexpectedly, we fail to find evidence that the disparities in training data lead to a meaningful difference in prediction quality for alleles not present in the training data. We attempt to explain this result by mapping the HLA sequence space to determine the sequence diversity of the training dataset. Furthermore, we link the residues which have the greatest impact on NetMHCpan predictions to structural features for three alleles (HLA-A*34:01, HLA-C*04:03, HLA-DRB1*12:02). [ABSTRACT FROM AUTHOR]

The immune system is as much shaped by the pressure of pathogens as it is by evolutionary trade-offs that constrain its structure and function. A perfect example comes from the major histocompatibility complex (MHC), molecules that initiate adaptive immune response by presentation of foreign antigens to T cells. The remarkable, population-level polymorphism of MHC genes is assumed to result mainly from a co-evolutionary arms race between hosts and pathogens, while the limited, within-individual number of functional MHC loci is thought to be the consequence of an evolutionary trade-off between enhanced pathogen recognition and excessive T cell depletion during negative selection in the thymus. Certain mathematical models and infection studies suggest that an intermediate individual MHC diversity would thus be optimal. A recent, more direct test of this hypothesis has shown that the effects of MHC diversity on T-cell receptor (TCR) repertoires may differ between MHC classes, supporting the depletion model only for MHC class I. Here, we used the bank vole (Myodes=Cletronomys glareolus), a rodent species with variable numbers of expressed MHC genes, to test how an individual MHC diversity influences the proportions and TCR repertoires of responding T cell subsets. We found a nonlinear relationship between MHC diversity and T cell proportions (with intermediate MHC numbers coinciding with the largest T cell proportions), perhaps reflecting an optimality effect of balanced positive and negative thymic selection. The association was strongest for the relationship between MHC class I and splenic CD8+ T cells. The CD8+ TCR richness alone was unaffected by MHC class I diversity, suggesting that MHC class I expansion may be limited by decreasing T cell counts, rather than by direct depletion of TCR richness. In contrast, CD4+ TCR richness was positively correlated with MHC class II diversity, arguing against a universal TCR depletion. It also suggests that different evolutionary forces or trade-offs may limit the within-individual expansion of the MHC class II loci. [ABSTRACT FROM AUTHOR]

Gene expression analysis enhances proper cancer subtyping, a better understanding of the molecular characteristics of cancer, and strategies for precision medicine. However, salivary gland cancer (SGC) subtyping remains largely unexplored because of its rarity and diverse histopathological and immunological characteristics. This study aimed to determine whether the histological origin and immunological characteristics of SGC subtypes are intrinsic tumor immunity factors. We performed immune profiling of 94 RNA-seq of SGC tissues and found that the SGCs that originated from the excretory duct (ED), such as the salivary duct and mucoepidermoid carcinomas, exhibit higher immunity than those from the intercalated duct (ID), such as the adenoid cystic and myoepithelial carcinomas, based on the computationally predicted immune score (p < 0.001), immune cell enrichment in the tumor immune microenvironment (TIME) (p < 0.001), T-cell receptor diversity (p < 0.001), and expression of signal I (major histocompatibility complex, MHC, p < 0.001) and signal II (co-stimulatory, p < 0.001 and co-inhibitory, p < 0.001) genes. Further analysis revealed that tolerogenic dendritic cell-induced dysfunctional T-cell populations and T-cell exclusion in the TIME are the major immune evasive mechanisms of the ED-and ID-derived SGCs, respectively. [ABSTRACT FROM AUTHOR]

Superantigens are virulence factors secreted by microorganisms that can cause various immune diseases, such as overactivating the immune system, resulting in cytokine storms, rheumatoid arthritis, and multiple sclerosis. Some studies have demonstrated that superantigens do not require intracellular processing and instated bind as intact proteins to the antigen-binding groove of major histocompatibility complex II on antigen-presenting cells, resulting in the activation of T cells with different T-cell receptor Vβ and subsequent overstimulation. To combat superantigen-mediated diseases, researchers have employed different approaches, such as antibodies and simulated peptides. However, due to the complex nature of superantigens, these approaches have not been entirely successful in achieving optimal therapeutic outcomes. CD28 interacts with members of the B7 molecule family to activate T cells. Its mimicking peptide has been suggested as a potential candidate to block superantigens, but it can lead to reduced T-cell activity while increasing the host's infection risk. Thus, this review focuses on the use of drug delivery methods to accurately target and block superantigens, while reducing the adverse effects associated with CD28 mimic peptides. We believe that this method has the potential to provide an effective and safe therapeutic strategy for superantigen-mediated diseases. [ABSTRACT FROM AUTHOR]