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Background: Dialysis patients are susceptible to developing severe coronavirus disease 2019 (COVID-19) due to hypoimmunity. Antibody titers against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) after the primary vaccinations are lower in hemodialysis (HD) patients than in healthy individuals. This study aimed to evaluate the effect of a SARS-CoV-2 booster vaccination in HD and peritoneal dialysis (PD) patients based on antibody titers and cellular and humoral immunity. Methods: Participants of the control, HD, and PD groups were recruited from 12 facilities. SARS-CoV-2 antigen-specific cytokine and IgG-antibody levels were measured. Regulatory T cells and memory B cells were counted using flow cytometry at 6 months after primary vaccination with BNT162b2 and 3 weeks after the booster vaccination in HD and PD patients and compared with those of a control group. Results: Booster vaccination significantly enhanced the levels of antibodies, cytokines, and memory B cells in three groups. The HD group showed significantly higher levels of IgG-antibodies, IL-1β, IL-2, IL-4, IL-17, and memory B cells than those in the control group at 3 weeks after the booster dose. The PD group tended to show similar trends to HD patients but had similar levels of IgG-antibodies, cytokines, and memory B cells to the control group. Conclusions: HD patients had significantly stronger cellular and humoral immune responses than the control 3 weeks after the booster dose. Our findings will help in developing better COVID-19 vaccination strategies for HD and PD patients. [ABSTRACT FROM AUTHOR]

Observational studies suggested that immune system disorder is associated with depression. However, the causal association has not been fully elucidated. Thus, we aim to assess the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. We extracted genetic variances of immune cell traits from a large publicly available genome-wide association study (GWAS) involving 3757 participants and depression from a GWAS containing 246,363 cases and 561,190 controls of European ancestry. Inverse variance weighting (IVW) was performed as the MR primary analysis. Simultaneously apply MR-Egger and weighted median as supplementary enhancements to the final result. We further performed heterogeneity and horizontal pleiotropy test to validate the main MR results. Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD − CD38 dim B cell (OR = 1.019, 95 % CI = 1.010–1.028, P = 1.24 × 10−5), CD45RA − CD4 + T cell Absolute Count (OR = 0.974, 95 % CI = 0.962–0.986, P = 3.88 × 10−5), CD40 on CD14 − CD16 + monocyte (OR = 0.987, 95 % CI = 0.981–0.993, P = 2.1 × 10−4), CD27 on switched memory B cell (OR = 1.015, 95 % CI = 1.006–1.023, P = 2.6 × 10−4), CD27 on IgD − CD38 − B cell (OR = 1.017, 95 % CI = 1.008–1.027, P = 3.1 × 10−4). Our findings shed light on the intricate interaction pattern between the immune system and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression. • This study aims to explore the causality of the associations of immune cell profiles with risk of depression through Mendelian randomization analysis. • Five immunophenotypes were identified to be significantly associated with depression risk: CD27 on IgD- CD38dim B cell, CD45RA- CD4+ T cell Absolute Count, CD40 on CD14- CD16+ monocyte, CD27 on switched memory B cell, CD27 on IgD- CD38- B cell. • Our findings shed light on the intricate interaction pattern between the immune cells and depression, offering a novel direction for researchers to investigate the underlying biological mechanisms of depression. [ABSTRACT FROM AUTHOR]

Latent human cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune‐compromised individuals. Although T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in hCMV immunity is lacking. Here, in an unbiased manner, we characterized over 8000 hCMV‐reactive peripheral memory T cells isolated from seropositive human donors, at a single‐cell resolution by analysing their single‐cell transcriptomes paired with the T cell antigen receptor (TCR) repertoires. The hCMV‐reactive T cells were highly heterogeneous and consisted of different developmental and functional memory T cell subsets such as, long‐term memory precursors and effectors, T helper‐17, T regulatory cells (TREGs) and cytotoxic T lymphocytes (CTLs) of both CD4 and CD8 origin. The hCMV‐specific TREGs, in addition to being enriched for molecules known for their suppressive functions, showed enrichment for the interferon response signature gene sets. The hCMV‐specific CTLs were of two types, the pre‐effector‐ and effector‐like. The co‐clustering of hCMV‐specific CD4‐CTLs and CD8‐CTLs in both pre‐effector as well as effector clusters suggest shared transcriptomic signatures between them. The huge TCR clonal expansion of cytotoxic clusters suggests a dominant role in the protective immune response to CMV. The study uncovers the heterogeneity in the hCMV‐specific memory T cells revealing many functional subsets with potential implications in better understanding of hCMV‐specific T cell immunity. The data presented can serve as a knowledge base for designing vaccines and therapeutics. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Lung adenocarcinoma (LUAD) is the most common type of lung cancer and closely associated with the immune system. Emerging evidence suggests that blood immune cell phenotypes in patients with LUAD may undergo alterations. Nevertheless, the limited amount of relevant research makes it difficult to understand the causal links between LUAD and changes in the immune cells. This study aimed to reveal the potential causal relationships between 731 immune cell phenotypes and LUAD.A bidirectional two‐sample Mendelian randomization (MR) analysis was used to clarify causal relationships. Four types of immune phenotypes, absolute cell counts, relative cell counts, median fluorescence intensities (MFIs) of surface antigens, and morphological parameters, were investigated in this study. Heterogeneity tests, horizontal pleiotropy tests, and leave‐one‐out analyses were performed to validate the reliability of our study.A total of 26 immune cell characteristics were identified as contributing to the occurrence of LUAD. Memory B cells, IgD−CD38br cells, CD4+ regulatory T cells (Tregs), and plasmacytoid dendritic cells (DCs) may play a role in the development of LUAD. Through reverse MR, our study discovered that the presence of LUAD also induced changes in the expression levels of 16 immune cell traits involving specific surface markers and various types of immune cells, some of which pertain to antigen presentation and immune activation processes.Our study demonstrated causal links between several immune cell phenotypes and LUAD, thereby providing indications of the potentially oncogenic physiological state and early screening biomarkers for future research. [ABSTRACT FROM AUTHOR]

Background: Nonspecific Orbital Inflammation (NSOI) represents a persistent and idiopathic proliferative inflammatory disorder, characterized by polymorphous lymphoid infiltration within the orbit. The transcription factor Interferon Regulatory Factor 8 (IRF8), integral to the IRF protein family, was initially identified as a pivotal element for the commitment and differentiation of myeloid cell lineage. Serving as a central regulator of innate immune receptor signaling, IRF8 orchestrates a myriad of functions in hematopoietic cell development. However, the intricate mechanisms underlying IRF8 production remain to be elucidated, and its potential role as a biomarker for NSOI is yet to be resolved. Methods: IRF8 was extracted from the intersection analysis of common DEGs of GSE58331 and GSE105149 from the GEO and immune- related gene lists in the ImmPort database using The Lasso regression and SVM-RFE analysis. We performed GSEA and GSVA with gene sets coexpressed with IRF8, and observed that gene sets positively related to IRF8 were enriched in immune-related pathways. To further explore the correlation between IRF8 and immune-related biological process, the CIBERSORT algorithm and ESTIMATE method were employed to evaluate TME characteristics of each sample and confirmed that high IRF8 expression might give rise to high immune cell infiltration. Finally, the GSE58331 was utilized to confirm the levels of expression of IRF8. Results: Among the 314 differentially expressed genes (DEGs), some DEGs were found to be significantly different. With LASSO and SVM-RFE algorithms, we obtained 15 hub genes. For biological function analysis in IRF8, leukocyte mediated immunity, leukocyte cell-cell adhesion, negative regulation of immune system process were emphasized. B cells naive, Macrophages M0, Macrophages M1, T cells CD4 memory activated, T cells CD4 memory resting, T cells CD4 naive, and T cells gamma delta were shown to be positively associated with IRF8. While, Mast cells resting, Monocytes, NK cells activated, Plasma cells, T cells CD8, and T cells regulatory (Tregs) were shown to be negatively linked with IRF8. The diagnostic ability of the IRF8 in differentiating NSOI exhibited a good value. Conclusions: This study discovered IRF8 that are linked to NSOI. IRF8 shed light on potential new biomarkers for NSOI and tracking its progression. [ABSTRACT FROM AUTHOR]

Background: Immunoregulatory drugs regulate the ubiquitin-proteasome system, which is the main treatment for multiple myeloma (MM) at present. In this study, bioinformatics analysis was used to construct the risk model and evaluate the prognostic value of ubiquitination-related genes in MM. Methods and results: The data on ubiquitination-related genes and MM samples were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The consistent cluster analysis and ESTIMATE algorithm were used to create distinct clusters. The MM prognostic risk model was constructed through single-factor and multiple-factor analysis. The ROC curve was plotted to compare the survival difference between high- and low-risk groups. The nomogram was used to validate the predictive capability of the risk model. A total of 87 ubiquitination-related genes were obtained, with 47 genes showing high expression in the MM group. According to the consistent cluster analysis, 4 clusters were determined. The immune infiltration, survival, and prognosis differed significantly among the 4 clusters. The tumor purity was higher in clusters 1 and 3 than in clusters 2 and 4, while the immune score and stromal score were lower in clusters 1 and 3. The proportion of B cells memory, plasma cells, and T cells CD4 naïve was the lowest in cluster 4. The model genes KLHL24, HERC6, USP3, TNIP1, and CISH were highly expressed in the high-risk group. AICAr and BMS.754,807 exhibited higher drug sensitivity in the low-risk group, whereas Bleomycin showed higher drug sensitivity in the high-risk group. The nomogram of the risk model demonstrated good efficacy in predicting the survival of MM patients using TCGA and GEO datasets. Conclusions: The risk model constructed by ubiquitination-related genes can be effectively used to predict the prognosis of MM patients. KLHL24, HERC6, USP3, TNIP1, and CISH genes in MM warrant further investigation as therapeutic targets and to combat drug resistance. [ABSTRACT FROM AUTHOR]

Background: Neuronal ferroptosis is closely related to the disease of the nervous system, and the objective of the present study was to recognize and verify the potential ferroptosis-related genes to forecast the neurological outcome after cardiac arrest. Methods: Cardiac Arrest-related microarray datasets GSE29540 and GSE92696 were downloaded from GEO and batch normalization of the expression data was performed using "sva" of the R package. GSE29540 was analyzed to identify DEGs. Venn diagram was applied to recognize ferroptosis-related DEGs from the DEGs. Subsequently, The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were performed, and PPI network was applied to screen hub genes. Receiver operating characteristic (ROC) curves were adopted to determine the predictive value of the biomarkers, and the GSE92696 dataset was applied to further evaluate the diagnostic efficacy of the biomarkers. We explore transcription factors and miRNAs associated with hub genes. The "CIBERSORT" package of R was utilized to analyse the proportion infiltrating immune cells. Finally, validated by a series of experiments at the cellular level. Results: 112 overlapping ferroptosis-related DEGs were further obtained via intersecting these DEGs and ferroptosis-related genes. The GO and KEGG analysis demonstrate that ferroptosis-related DEGs are mainly involved in response to oxidative stress, ferroptosis, apoptosis, IL-17 signalling pathway, autophagy, toll-like receptor signalling pathway. The top 10 hub genes were selected, including HIF1A, MAPK3, PPARA, IL1B, PTGS2, RELA, TLR4, KEAP1, SREBF1, SIRT6. Only MAPK3 was upregulated in both GSE29540 and GAE92696. The AUC values of the MAPK3 are 0.654 and 0.850 in GSE29540 and GSE92696 respectively. The result of miRNAs associated with hub genes indicates that hsa-miR-214-3p and hsa-miR-483-5p can regulate the expression of MAPK3. MAPK3 was positively correlated with naive B cells, macrophages M0, activated dendritic cells and negatively correlated with activated CD4 memory T cells, CD8 T cells, and memory B cells. Compared to the OGD4/R24 group, the OGD4/R12 group had higher MAPK3 expression at both mRNA and protein levels and more severe ferroptosis. Conclusion: In summary, the MAPK3 ferroptosis-related gene could be used as a biomarker to predict the neurological outcome after cardiac arrest. Potential biological pathways provide novel insights into the pathogenesis of cardiac arrest. [ABSTRACT FROM AUTHOR]

Background Variability in vaccine responsiveness among young children is poorly understood. Methods Nasopharyngeal secretions were collected in the first weeks of life for measurement of cytokines/chemokines seeking a biomarker, and blood samples were collected at age 1 year to identify vaccine responsiveness status, defined as low vaccine responder (LVR), normal vaccine responder (NVR), and high vaccine responder (HVR), to test for vaccine antigen–induced immune memory and for antigen-presenting cell (APC) function. Results Significantly lower specific cytokine/chemokine levels as biosignatures, measurable in nasopharyngeal secretions at infant age 1–3 weeks, predicted LVR status compared to NVR and HVR children. Antibiotic exposures were correlated with increased occurrence of LVR. At age 1 year, LVRs had fewer CD4+ T-helper 1 and T-helper 2 memory cells responsive to specific vaccine antigens. APC responses observed among LVRs, both at rest and in response to Toll-like receptor 7/8 stimulation by R848, were suboptimal, suggesting that altered innate immunity may contribute to immune deficiency in LVRs. Conclusions Cytokine biosignatures in the first weeks of life may predict vaccine responsiveness in children during the first year of life. Antibiotic exposure is associated with LVR in children. CD4+ T-cell memory induction and APC deficiencies occur in LVR children. [ABSTRACT FROM AUTHOR]

Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon rechallenge with the same pathogen, their impact on susceptibility to unrelated diseases is unclear. We identify a subset of memory T helper 1 (Th1) cells termed innate acting memory T (TIA) cells that originate from a viral infection and produce IFN-γ with innate kinetics upon heterologous challenge in vivo. Activation of memory TIA cells is induced in response to IL-12 in combination with IL-18 or IL-33 but is TCR independent. Rapid IFN-γ production by memory TIA cells is protective in subsequent heterologous challenge with the bacterial pathogen Legionella pneumophila. In contrast, antigen-independent reactivation of CD4+ memory TIA cells accelerates disease onset in an autoimmune model of multiple sclerosis. Our findings demonstrate that memory Th1 cells can acquire additional TCR-independent functionality to mount rapid, innate-like responses that modulate susceptibility to heterologous challenges. [ABSTRACT FROM AUTHOR]

• Higher doses of Ad26.COV2.S tended to be more immunogenic and more reactogenic than lower doses. • VNAs and S-bAbs persisted for at least 6 months after just 1 dose of Ad26.COV2.S 5 × 1010 vp. • Immune responses increased when the time interval between dose 1 and dose 2 increased. • Rapid, marked responses in all groups after vaccine antigen exposure indicate immune memory. • Durable immune responses were observed in all groups up to at least 6 months post vaccine antigen exposure. A single dose of Ad26.COV2.S is well-tolerated and effective in preventing moderate-to-severe disease outcomes due to COVID-19. We evaluated the impact of dose level, number of doses, and dose interval on immunogenicity, reactogenicity, and safety of Ad26.COV2.S in adults. Anamnestic responses were also explored. This randomised, double-blind, placebo-controlled, Phase 2a study was conducted in adults aged 18–55 years and ≥ 65 years (NCT04535453). Four dose levels (1.25 × 1010, 2.5 × 1010, 5 × 1010, and 1 × 1011 viral particles [vp], single and 2-dose schedules, and dose intervals of 56 and 84 days, were assessed. Four or 6 months post-primary vaccination, Ad26.COV2.S 1.25 × 1010 vp was given to evaluate anamnestic responses. Humoral and cell-mediated immune responses were measured. Reactogenicity and safety were assessed in all participants. All Ad26.COV2.S schedules induced humoral responses with evidence of a dose response relationship. A single dose of Ad26.COV2.S (5 × 1010 vp) induced antibody and cellular immune responses that persisted for up to at least 6 months. In the 2-dose regimens, antibody responses were higher than 1-dose regimens at comparable dose levels, and the magnitude of the immune response increased when the interval between doses was increased (84 days vs 56 days). Rapid, marked immune responses were observed in all groups after vaccine antigen exposure indicating immune memory. Durable immune responses were observed in all groups for up to at least 6 months post-antigen exposure. Strong and consistent correlations between neutralising and binding antibodies were observed CD4 + and CD8 + T cell responses were similar after all regimens. Reactogenicity within 7 days post-vaccination tended to be dose-related. The study supports the primary, single dose schedule with Ad26.COV2.S at 5 × 1010 vp and homologous booster vaccination after a 6 month interval. Rapid and marked responses to vaccine antigen exposure indicate induction of immune memory by 1- and 2-dose primary vaccination. [ABSTRACT FROM AUTHOR]

Invertebrates lack the immune machinery underlying vertebrate-like acquired immunity. However, in many insects past infection by the same pathogen can 'prime' the immune response, resulting in improved survival upon reinfection. Here, we investigated the mechanistic basis and epidemiological consequences of innate immune priming in the fruit fly Drosophila melanogaster when infected with the gram-negative bacterial pathogen Providencia rettgeri. We find that priming in response to P. rettgeri infection is long-lasting and sexually dimorphic response. We further explore the epidemiological consequences of immune priming and find it has the potential to curtail pathogen transmission by reducing pathogen shedding and spread. The enhanced survival of individuals previously exposed to a non-lethal bacterial inoculum coincided with a transient decrease in bacterial loads, and we provide strong evidence that the effect of priming requires the IMD-responsive antimicrobial-peptide Diptericin-B in the fat body. Further, we show that while Diptericin B is the main effector of bacterial clearance, it is not sufficient for immune priming, which requires regulation of IMD by peptidoglycan recognition proteins. This work underscores the plasticity and complexity of invertebrate responses to infection, providing novel experimental evidence for the effects of innate immune priming on population-level epidemiological outcomes. Author summary: When we are vaccinated, our immune response is able to respond quickly if we are ever exposed to the same pathogen in the future. Unlike humans, the immune systems of invertebrates, such as insects, are not capable of the same type of specific immune memory. However, much work has shown that insects previously exposed to an inactivated pathogen will fare better if they are re-infected–a phenomenon broadly called "immune priming". How insects are able to do this is an exciting focus of current research. We investigated immune priming in the fruit fly, a powerful model system for infection and immunity. We found that exposure to an inactivated form of the bacterial fly pathogen Providencia rettgeri resulted in flies surviving a subsequent live infection. This effect lasted several days, was stronger in male flies, and was seen in different fly genetic backgrounds. We uncovered that priming requires a specific immune response in the fly fat-body (the equivalent to a fly 'liver') that produces an antimicrobial protein called Diptericin. We also found that primed flies were able to keep pathogen growth lower, and that this reduced their ability to spread the infection to other flies. [ABSTRACT FROM AUTHOR]

Background and purpose: The immune response changes during aging and the progression of Alzheimer's disease (AD) and related dementia (ADRD). Terminally differentiated effector memory T cells (called TEMRA) are important during aging and AD due to their cytotoxic phenotype and association with cognitive decline. However, it is not clear if the changes seen in TEMRAs are specific to AD-related cognitive decline specifically or are more generally correlated with cognitive decline. This study aimed to examine whether TEMRAs are associated with cognition and plasma biomarkers of AD, neurodegeneration, and neuroinflammation in a community-based cohort of older adults. Methods: Study participants from a University of Kentucky Alzheimer's Disease Research Center (UK-ADRC) community-based cohort of aging and dementia were used to test our hypothesis. There were 84 participants, 44 women and 40 men. Participants underwent physical examination, neurological examination, medical history, cognitive testing, and blood collection to determine plasma biomarker levels (Aβ42/Aβ40 ratio, total tau, Neurofilament Light chain (Nf-L), Glial Fibrillary Acidic Protein (GFAP)) and to isolate peripheral blood mononuclear cells (PBMCs). Flow cytometry was used to analyze PBMCs from study participants for effector and memory T cell populations, including CD4+ and CD8+ central memory T cells (TCM), Naïve T cells, effector memory T cells (TEM), and effector memory CD45RA+ T cells (TEMRA) immune cell markers. Results: CD8+ TEMRAs were positively correlated with Nf-L and GFAP. We found no significant difference in CD8+ TEMRAs based on cognitive scores and no associations between CD8+ TEMRAs and AD-related biomarkers. CD4+ TEMRAs were associated with cognitive impairment on the MMSE. Gender was not associated with TEMRAs, but it did show an association with other T cell populations. Conclusion: These findings suggest that the accumulation of CD8+ TEMRAs may be a response to neuronal injury (Nf-L) and neuroinflammation (GFAP) during aging or the progression of AD and ADRD. As our findings in a community-based cohort were not clinically-defined AD participants but included all ADRDs, this suggests that TEMRAs may be associated with changes in systemic immune T cell subsets associated with the onset of pathology. [ABSTRACT FROM AUTHOR]

Immunotoxicity remains a major hindrance to chemotherapy in cancer therapy. Nanocarriers may alleviate the immunotoxicity, but the optimal design remains unclear. Here, we created two variants of maytansine (DM1)-loaded synthetic high-density lipoproteins (D-sHDL) with either physically entrapped (ED-sHDL) or chemically conjugated (CD-sHDL) DM1. We found that CD-sHDL showed less accumulation in the tumor draining lymph nodes (DLNs) and femur, resulting in a lower toxicity against myeloid cells than ED-sHDL via avoiding scavenger receptor class B type 1 (SR-B1)-mediated DM1 transportation into the granulocyte-monocyte progenitors and dendritic cells. Therefore, higher densities of lymphocytes in the tumors, DLNs, and blood were recorded in mice receiving CD-sHDL, leading to a better efficacy and immune memory of CD-sHDL against colon cancer. Furthermore, liposomes with conjugated DM1 (CD-Lipo) showed lower immunotoxicity than those with entrapped drug (ED-Lipo) through the same mechanism after apolipoprotein opsonization. Our findings highlight the critical role of drug loading patterns in dictating the biological fate and activity of nanomedicine. [ABSTRACT FROM AUTHOR]

Background: Long QT Syndrome (LQTS) and Beckwith-Wiedemann Syndrome (BWS) are complex disorders with unclear origins, underscoring the need for in-depth molecular investigations into their mechanisms. The main aim of this study is to identify the shared key genes between LQTS and BWS, shedding light on potential common molecular pathways underlying these syndromes. Methods: The LQTS and BWS datasets are available for download from the GEO database. Differential expression genes (DEGs) were identified. Weighted gene co-expression network analysis (WGCNA) was used to detect significant modules and central genes. Gene enrichment analysis was performed. CIBERSORT was used for immune cell infiltration analysis. The predictive protein interaction (PPI) network of core genes was constructed using STRING, and miRNAs regulating central genes were screened using TargetScan. Results: Five hundred DEGs associated with Long QT Syndrome and Beckwith-Wiedemann Syndrome were identified. GSEA analysis revealed enrichment in pathways such as T cell receptor signaling, MAPK signaling, and adrenergic signaling in cardiac myocytes. Immune cell infiltration indicated higher levels of memory B cells and naive CD4 T cells. Four core genes (CD8A, ICOS, CTLA4, LCK) were identified, with CD8A and ICOS showing low expression in the syndromes and high expression in normal samples, suggesting potential inverse regulatory roles. Conclusion: The expression of CD8A and ICOS is low in long QT syndrome and Beckwith-Wiedemann syndrome, indicating their potential as key genes in the pathogenesis of these syndromes. The identification of shared key genes between LQTS and BWS provides insights into common molecular mechanisms underlying these disorders, potentially facilitating the development of targeted therapeutic strategies. [ABSTRACT FROM AUTHOR]

Memory T cells demonstrate superior in vivo persistence and antitumor efficacy. However, methods for manufacturing less differentiated T cells are not yet well-established. Here, we show that producing chimeric antigen receptor (CAR)-T cells using berbamine (BBM), a natural compound found in the Chinese herbal medicine Berberis amurensis, enhances the antitumor efficacy of CAR-T cells. BBM is identified through cell-based screening of chemical compounds using induced pluripotent stem cell-derived T cells, leading to improved viability with a memory T cell phenotype. Transcriptomics and metabolomics using stem cell memory T cells reveal that BBM broadly enhances lipid metabolism. Furthermore, the addition of BBM downregulates the phosphorylation of p38 mitogen-activated protein kinase and enhanced mitochondrial respiration. CD19-CAR-T cells cultured with BBM also extend the survival of leukaemia mouse models due to their superior in vivo persistence. This technology offers a straightforward approach to enhancing the antitumor efficacy of CAR-T cells. When used in CAR-T cell processing, the plant alkaloid berbamine prolongs the survival of leukemic animals by boosting CAR-T cell viability, memory phenotype, and persistence by modulating cellular metabolism, including mitochondrial respiration. [ABSTRACT FROM AUTHOR]

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones. [ABSTRACT FROM AUTHOR]

Donor-reactive memory cells represent a barrier to long-term kidney graft survival. A better understanding of regulatory mechanisms that counterbalance alloreactive memory responses may help to identify patients with operational tolerance. This prospective study investigated the equilibrium between memory T-cell subsets and regulatory T or B cells (Tregs, Bregs) in peripheral blood of kidney transplant recipients with operational tolerance (N = 8), chronic rejection (N = 8), and different immunosuppressive treatment regimens (N = 81). Patients on hemodialysis and healthy individuals served as controls (N = 50). In addition, the expression of Treg- and Breg-associated molecule genes was analyzed. Patients with chronic rejection showed a disrupted memory T-cell composition with a significantly higher frequency of circulating CD8+ terminally differentiated effector memory (TEMRA) T cells than patients with operational tolerance, patients on hemodialysis, or healthy controls (P < 0.001). Low frequency of CD8+ TEMRA and high frequency of Tregs and transitional Bregs were found in operationally tolerant patients. Consequently, operationally tolerant patients showed, as compared to all other transplant recipients with different immunosuppressive regiments, the lowest ratios between CD8+ TEMRA T cells and Tregs or Bregs (for both P < 0.001). Moreover, a specific peripheral blood transcription pattern was found in operationally tolerant patients with an increased expression of Breg- and Treg-associated genes CD22 and FoxP3 and a decreased FcγRIIA/FcγRIIB transcript ratio (for all P < 0.001). In conclusion, monitoring the balance between circulating CD8+ TEMRA T cells and regulatory cell subsets and their transcripts may help to distinguish transplant recipients with operational tolerance from recipients at risk of graft loss. We show that a balance between effector mechanisms mediated by CD8 + TEMRA T cells and regulatory cell populations such as Bregs, Tregs, or naive T cells determines long-term kidney graft survival. Monitoring the balance between circulating CD8 + TEMRA T cells and regulatory cell subsets and their transcripts may help to distinguish transplant recipients with OT from recipients at risk of graft loss. Our study provides evidence in favor of regulatory mechanisms that counterbalance alloreactive memory immune responses and may encourage further investigations whether the ratio between CD8 + TEMRA T cells and Tregs or Bregs can help to safely guide minimization of immunosuppression in selected patients. Graphical Abstract [ABSTRACT FROM AUTHOR]

Sarcoidosis results from a combination of genetic variants and environmental factors but its exact cause remains unknown. Evidence highlights a major role of monocytes as important drivers of sarcoidosis immunopathogenesis. The emerging concept of trained immunity opens new perspectives for the comprehension of sarcoidosis pathology, with a particular presumed role played by immune metabolism and epigenetics. We posit that maladaptive innate immune training may drive sarcoidosis pathogenesis. The confirmation of maladaptive innate immune training in sarcoidosis might allow the development of new candidate therapeutic strategies. The pathogenesis of sarcoidosis, an immune-mediated granulomatous disease, has long remained elusive. Recent discoveries on trained immunity might help decipher immunological mechanisms underlying the disease which in turn may inform novel putative treatment options. Sarcoidosis is a chronic immune disease of unknown origin for which we still lack an immunological framework unifying causal agents, host factors, and natural history of disease. Here, we discuss the initial triggers of disease, and how myeloid cells drive granuloma formation and contribute to immunopathogenesis. We highlight recent advances in our understanding of innate immune memory and propose the hypothesis that maladaptive innate immune training connects previous environmental exposure to granuloma maintenance and expansion. Lastly, we consider how this hypothesis may open novel therapeutic avenues, while corticosteroids remain the front-line treatment. [ABSTRACT FROM AUTHOR]

We have previously performed preclinical studies with the oxidized mannan-conjugated peptide MOG35–55 (OM-MOG35–55) in vivo (EAE mouse model) and in vitro (human peripheral blood) and demonstrated that OM-MOG35–55 suppresses antigen-specific T cell responses associated with autoimmune demyelination. Based on these results, we developed different types of dendritic cells (DCs) from the peripheral blood monocytes of patients with multiple sclerosis (MS) or healthy controls presenting OM-MOG35–55 or MOG-35–55 to autologous T cells to investigate the tolerogenic potential of OM-MOG35–55 for its possible use in MS therapy. To this end, monocytes were differentiated into different DC types in the presence of IL-4+GM-CSF ± dexamethasone (DEXA) ± vitamin D3 (VITD3). At the end of their differentiation, the DCs were loaded with peptides and co-cultured with T cells +IL-2 for 4 antigen presentation cycles. The phenotypes of the DC and T cell populations were analyzed using flow cytometry and the secreted cytokines using flow cytometry or ELISA. On day 8, the monocytes had converted into DCs expressing the typical markers of mature or immature phenotypes. Co-culture of T cells with all DC types for 4 antigen presentation cycles resulted in an increase in memory CD4+ T cells compared to memory CD8+ T cells and a suppressive shift in secreted cytokines, mainly due to increased TGF-β1 levels. The best tolerogenic effect was obtained when patient CD4+ T cells were co-cultured with VITD3-DCs presenting OM-MOG35–55, resulting in the highest levels of CD4+PD-1+ T cells and CD4+CD25+Foxp3+ Τ cells. In conclusion, the tolerance induction protocols presented in this work demonstrate that OM-MOG35–55 could form the basis for the development of personalized therapeutic vaccines or immunomodulatory treatments for MS. [ABSTRACT FROM AUTHOR]

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs. [ABSTRACT FROM AUTHOR]

Background: Ocrelizumab (OCR) is an anti-CD20 monoclonal antibody approved for the treatment of relapsing-remitting and primary-progressive multiple sclerosis (MS). We aimed to evaluate the effectiveness of an individualized OCR extended interval dosing (EID), after switching from standard interval dosing (SID). Methods: This was a retrospective, observational, single-centre study including MS patients regularly followed at the Neurocenter of Southern Switzerland. After a cumulative OCR dose ⩾1200 mg, stable patients were switched to EID (OCR infusions following CD19+ 27+ memory B cell repopulation). Results: A total of 128 patients were included in the study, and 113 (88.3%) were switched to EID with a median interval of 9.9 (8.8–11.8) months between infusions. No clinical relapses occurred; 2 (1.8%) patients experienced disability worsening. Three (2.7%) and 2 (1.8%) patients experienced new T2 brain and spinal lesions, respectively. There was a mild decrease in IgG and IgM concentrations during both SID and EID OCR regimens (β = −0.23, p = 0.001 and β = −0.07, p < 0.001, respectively). Conclusion: Switch to personalized dosing of OCR based on CD19+ 27+ memory B cell repopulation led to a great extension of the interval between infusions, with maintained clinical and radiological efficacy. Given the potential advantages in terms of safety and health costs, EID OCR regimens should be further investigated. [ABSTRACT FROM AUTHOR]

This document, titled "In This Issue," provides a summary of several articles published in the journal International Immunology. The first article discusses the reprogramming of T-cell metabolism to enhance T-cell immunotherapy, particularly in the context of solid tumors with an immunosuppressive metabolic microenvironment. The second article focuses on the crystal structure of the C-type lectin receptor CLEC12A and its potential diagnostic and therapeutic implications. The third article explores a novel approach to identify statin-mediated anti-cancer effects by analyzing the effects of inhibiting HMGCR variants on lipid metabolism and immunotherapy. The fourth article investigates the role of glycan-mediated lymphocyte homing in experimental autoimmune encephalomyelitis (EAE) and its potential as a therapeutic target in multiple sclerosis (MS). Lastly, the fifth article examines the N-glycosylation of CD155 and its impact on NK cell activation, suggesting that therapeutic antibodies targeting CD155 may be more effective against tumors expressing N105-glycosylated CD155. [Extracted from the article]

Aim: Differential patterns of peripheral memory T cell subsets in nonalcoholic fatty liver disease (NAFLD) were assessed using flow cytometry (FCM) to elucidate their association with NAFLD severity and provide a new noninvasive method to sensitively detect the disease severity in addition to existing biomarkers. Methods: We assessed the differential frequencies of peripheral memory T cell subsets in 103 patients with NAFLD according to the degree of liver fibrosis (FIB) using FCM analysis. We focused on the following populations: CCR7+ CD45RA+ naïve T, CCR7+ CD45RA– central memory T cells (TCM), CCR7– CD45RA– effector memory T, and CCR7– CD45RA+ terminally differentiated effector memory T (TEMRA) cells in CD4+ and CD8+ T, Th1, Th2, and Th17 cells, respectively. To evaluate the pathological progression of the disease, these frequencies were also examined according to the degree of the NAFLD activity score (NAS). Results: Several significant correlations were observed between laboratory parameters and peripheral memory T lymphocyte frequencies according to the degree of liver FIB and NAS in NAFLD. In univariate and multivariate analyses, the frequency of CD8+ TEMRA cells predicted severe FIB, and the predictive power was validated in an independent cohort. Furthermore, the frequencies of several memory T cell subsets sensitively indicated the pathological progression of NAFLD (Th17 TCM: steatosis, CD4+ TCM: lobular inflammation, and CD8+ TEMRA and effector memory T cells: hepatocellular ballooning). Conclusions: Our results suggest that the analysis of peripheral memory T lymphocyte frequencies can noninvasively predict severe FIB and sensitively indicate the pathological progression of NAFLD. [ABSTRACT FROM AUTHOR]

Introduction: Stroke is one of the common diseases that pose a severe threat to human health, with immune cells playing a crucial role in its onset and recovery. However, the specific mechanisms and causal relationships of different immune cell groups in various clinical stroke subtypes are unclear. This study explored the causal relationship between immune cells and stroke and its subtypes using Mendelian randomization (MR) analysis. Methods: Data from genome-wide association studies were analyzed using inverse-variance weighted (IVW), MR-Egger, and weighted median methods for MR analysis, along with heterogeneity tests, sensitivity analysis, and pleiotropy analysis. Results: CD45RA+CD28−CD8+ T cell %T cell (OR 1.002, 95% CI 1.001–1.003; PFDR = 0.02), CD27 on CD24+CD27+ B cell (OR 1.127, 95% CI 1.061–1.198; PFDR = 0.04), CD27 on IgD−CD38dim B cell (OR 1.138, 95% CI 1.076–1.203; PFDR = 0.005), and CD27 on switched memory B cell (OR 1.144, 95% CI 1.076–1.216; PFDR = 0.01) were found to increase the risk of large artery stroke. Switched memory B cell %lymphocyte (OR 1.206, 95% CI 1.103–1.318; PFDR = 0.02) increased the risk of small vessel stroke. Reverse MR analysis did not reveal any reverse causal associations. Furthermore, by substituting the outcome data, a secondary MR analysis was conducted to validate the primary findings. Conclusion: Our study reveals several causal links between immune phenotypes and stroke and its different subtypes, highlighting the complex interactions between the immune system and stroke. These findings provide new directions for further uncovering the biological basis of stroke and assist in advancing research on early interventions and treatment strategies. [ABSTRACT FROM AUTHOR]

The mitochondria are an important organelle in cells responsible for producing energy, and its abnormal function is closely related to the occurrence and development of osteoarthritis. Finding key genes associated with mitochondrial dysfunction in osteoarthritis can provide new ideas for the study of its pathogenesis. Firstly, 371 differential expressed genes (DEGs) were obtained through bioinformatics analysis of the GSE12021 and GSE55235 datasets in the GEO database, and 24 mitochondria-related DEGs (Mito-DEGs) were obtained by crossing differential genes with mitochondrial related genes. Next, KEGG and GO analysis of Mito-DEGs showed that upregulated Mito-DEGs were mainly enriched in small molecule catabolic process and tryptophan metabolism, while downregulated Mito-DEGs were mainly enriched in acetyl-CoA metabolic process and fatty acid biosynthesis. Furthermore, the key genes ME2 and MAOB were obtained through protein–protein interaction network analysis and lasso cox analysis of the 24 Mito-DEGs. In addition, the comparison results of immune cell scores showed differences between T cells CD4 memory resting, T cells regulatory (Tregs), Mast cells resting, and Mast cells activated in the OA group and the control group. More importantly, the potential regulatory mechanisms of key genes were studied through GSEA analysis and their correlation with immune infiltrating cells, immune checkpoints, m6A, and ferroptosis. Finally, in LPS-induced C28/I2 cells, silencing MAOB reduced inflammation injury and inhibited mitochondrial damage. Our research findings suggest that MAOB may hold potential as a target for the diagnosis and treatment of osteoarthritis. [ABSTRACT FROM AUTHOR]

The CliniMACS Prodigy closed system is widely used for the manufacturing of chimeric antigen receptor T cells (CAR-T cells). Our study presents an extensive immunophenotypic and functional characterization and comparison of the properties of anti-CD19 CAR-T cell products obtained during long (11 days) and short (7 days) manufacturing cycles using the CliniMACS Prodigy system, as well as cell products manufactured from different donor sources of T lymphocytes: from patients, from patients who underwent HSCT, and from haploidentical donors. We also present the possibility of assessing the efficiency of transduction by an indirect method. Seventy-six CD19 CAR-T cell products were manufactured using the CliniMACS Prodigy automated system. Immunophenotypic properties, markers of cell activation and exhaustion, antitumor, anti-CD19 specific activity in vitro of the manufactured cell products were evaluated. As an indirect method for assessing the efficiency of transduction, we used the method of functional assessment of cytokine secretion and expression of the CD107a marker after incubation of CAR-T cells with tumor targets. The CliniMACS Prodigy platform can produce a product of CD19 CAR-T cells with sufficient cell expansion (4.6 × 109 cells—median for long process [LP] and 1.6 × 109—for short process [SP]), transduction efficiency (43.5%—median for LP and 41.0%—for SP), represented mainly by T central memory cell population, with low expression of exhaustion markers, and with high specific antitumor activity in vitro. We did not find significant differences in the properties of the products obtained during the 7- and 11-day manufacturing cycles, which is in favor of reducing the duration of production to 7 days, which may accelerate CAR-T therapy. We have shown that donor sources for CAR-T manufacturing do not significantly affect the composition and functional properties of the cell product. This study demonstrates the possibility of using the CliniMACS Prodigy system with a shortened 7-day production cycle to produce sufficient amount of functional CAR-T cells. CAR transduction efficiency can be measured indirectly via functional assays. [ABSTRACT FROM AUTHOR]

Vaccination is essential for preventing and controlling infectious diseases, along with reducing mortality. Developing safe and versatile adjuvants to enhance humoral and cellular immune responses to vaccines remains a key challenge in vaccine development. Here, we designed hierarchical mesoporous MOF-801 (HM801) using a Cocamidopropyl betaine (CAPB) and a Pluronics F127 in an aqueous phase system. Meanwhile, we synthesized a novel SARS-CoV-2 nanovaccine (R@M@HM801) with a high loading capacity for both the STING agonist (MSA-2) and the Delta receptor binding domain (Delta-RBD) antigen. R@M@HM801 enhanced MSA-2 and RBD utilization and effectively co-delivered MSA-2 and RBD antigens to antigen-presenting cells in the draining lymph nodes, thereby promoting the activation of both T and B cells. Lymphocyte single-cell analysis showed that R@M@HM801 stimulated robust CD11b+CD4+ T cells, CXCR5+CD4+ T follicular helper (T fh), and durable CD4+CD44+CD62L−, CD8+CD44+CD62L− effector memory T cell (T EM) immune responses, and promoted the proliferative activation of CD26+ B cells in vivo. Meanwhile, R@M@HM801 induced stronger specific antibodies and neutralization of pseudovirus against Delta compared to the RBD + MAS-2 and RBD + MAS-2 + Alum vaccines. Our study demonstrated the efficacy of a hierarchical mesoporous HM801 and its potential immune activation mechanism in enhancing adaptive immune responses against viruses and other diseases. [Display omitted] • HM801 efficiently co-delivers MSA-2 and RBD antigens to DCs in lymph nodes, promotes maturation of DCs, and induces humoral and cellular immunity. • Single-cell analysis indicates a potential synergistic mechanism among DC cells, T cells, and B cells. • R@M@HM801 induces stronger specific antibody responses. • Our study provides new insights into the adjuvants based on hierarchical mesoporous MOFs. [ABSTRACT FROM AUTHOR]

[Display omitted] Chemo-immunotherapy, in which chemotherapeutic drugs activate immune system to suppress tumor growth and metastases, has great potential for clinical application. However, insufficient immunogenic cell death and serious side effects caused by tumor multidrug resistance and non-specific drug distribution, as well as inadequate and dysfunctional immune cells, greatly impair the effectiveness of chemo-immunotherapy. Herein, taking advantage of the functional diversity and structural programmability of nucleic acids, a DNA-based bioorthogonal nanoagonist is constructed to initiate and augment immune responses for robust chemo-immunotherapy. Benefiting from polyvalent targeting and template effects of DNA, the tailor-made nanoagonist shows prior bioorthogonal catalytic performance. Chemotherapeutic drug is bioorthogonally synthesized in situ under the catalysis of the nanoagonist, maximizing immunogenic cell death and minimizing systemic toxicity. The large amount of antigen and damage-associated molecular patterns released from dying tumor cells effectively initiates antitumor immunity. Meanwhile, the integration of high density of immunologic adjuvant can more effectively stimulate immune cells. The combination of bioorthogonal catalytic drug synthesis and immunostimulatory effect of DNA adjuvant not only destroys local primary tumors, but also eliminates distal metastasis. Moreover, the nanoagonist triggered the immune memory effect. The work extends the application of bioorthogonal chemistry to immunotherapy and provides a safe and powerful strategy for cancer chemo-immunotherapy. [ABSTRACT FROM AUTHOR]

Chronic infection with the hepatitis B virus (HBV) induces progressive hepatic impairment. Achieving complete eradication of the virus remains a formidable challenge. Cytotoxic T lymphocytes, specific to viral antigens, either exhibit a numerical deficiency or succumb to an exhausted state in individuals chronically afflicted with HBV. The comprehension of the genesis and dissemination of stem cell memory T cells (TSCMs) targeting HBV remains inadequately elucidated. We identified TSCMs in subjects with chronic HBV infection and scrutinized their efficacy in a murine model with human hepatocyte transplants, specifically the TK‐NOG mice. TSCMs were discerned in all subjects under examination. Introduction of TSCMs into the HBV mouse model precipitated a severe necro‐inflammatory response, resulting in the elimination of human hepatocytes. TSCMs may constitute a valuable tool in the pursuit of a remedial therapy for HBV infection. [ABSTRACT FROM AUTHOR]

The article focuses on Omas Müller's journey through profound depression and misdiagnosis, ultimately finding relief through a neuropsychiatrist's identification of autoimmune encephalitis, shedding light on a growing understanding of autoimmune conditions triggering psychosis and revolutionizing clinical psychiatry.

Background: Non-small cell lung cancer (NSCLC) is one of the predominant malignancies globally. Percutaneous thermal ablation (PTA) has gained widespread use among NSCLC patients, with the potential to elicit immune responses but limited therapeutic efficacies for advanced-stage disease. T-helper type 9 (Th9) cells are a subset of CD4+ effector T cells with robust and persistent anti-tumor effects. This study proposes to develop PTA-Th9 cell integrated therapy as a potential strategy for NSCLC treatment. Methods: The therapeutic efficacies were measured in mice models with subcutaneously transplanted, recurrence, or lung metastatic tumors. The tumor microenvironments (TMEs) were evaluated by flow cytometry. The cytokine levels were assessed by ELISA. The signaling molecules were determined by quantitative PCR and Western blotting. The translational potential was tested in the humanized NSCLC patient-derived xenograft (PDX) model. Results: We find that PTA combined with adoptive Th9 cell transfer therapy substantially suppresses tumor growth, recurrence, and lung metastasis, ultimately extending the survival of mice with NSCLC grafts, outperforming both PTA and Th9 cell transfer monotherapy. Analysis of TMEs indicates that combinatorial therapy significantly augments tumor-infiltrating Th9 cells, boosts anti-tumor effects of CD8+ T cells, and remodels tumor immunosuppressive microenvironments. Moreover, combinatorial therapy significantly strengthens the regional and circulation immune response of CD8+ T cells in mice with tumor lung metastasis and induces peripheral CD8+ T effector memory cells in mice with tumor recurrence. Mechanically, PTA reinforces the anti-tumor ability of Th9 cells primarily through upregulating interleukin (IL)-1β and subsequently activating the downstream STAT1/IRF1 pathway, which could be effectively blocked by intercepting IL-1β signaling. Finally, the enhanced therapeutic effect of combinatorial therapy is validated in humanized NSCLC PDX models. Conclusions: Collectively, this study demonstrates that combinatorial therapy displays robust and durable anti-tumor efficacy and excellent translational potential, offering excellent prospects for translation and emerging as a promising approach for NSCLC treatment. [ABSTRACT FROM AUTHOR]

Interleukin 32 (IL-32) is a potent multi-isoform proinflammatory cytokine, which is upregulated in people with HIV (PWH) and is associated with cardiovascular disease (CVD) risk. However, the impact of IL-32 isoforms on CD4 T-cell cardiotropism, a mechanism potentially contributing to heart inflammation, remains unknown. Here we show that IL-32 isoforms β and γ induce the generation of CCR4+CXCR3+ double positive (DP) memory CD4 T-cell subpopulation expressing the tyrosine kinase receptor c-Met, a phenotype associated with heart-homing of T cells. Our ex vivo studies on PWH show that the frequency of DP CD4 T cells is significantly higher in individuals with, compared to individuals without, subclinical atherosclerosis and that DP cells from antiretroviral-naive and treated individuals are highly enriched with HIV DNA. Together, these data demonstrate that IL-32 isoforms have the potential to induce heart-homing of HIV-infected CD4 T cells, which may further aggravate heart inflammation and CVD in PWH. [ABSTRACT FROM AUTHOR]

Background: In most cases, Zika virus (ZIKV) causes a self-limited acute illness in adults, characterized by mild clinical symptoms that resolve within a few days. Immune responses, both innate and adaptive, play a central role in controlling and eliminating virus-infected cells during the early stages of infection. Aim: To test the hypothesis that circulating T cells exhibit phenotypic and functional activation characteristics during the viremic phase of ZIKV infection. Methods: A comprehensive analysis using mass cytometry was performed on peripheral blood mononuclear cells obtained from patients with acute ZIKV infection (as confirmed by RT-PCR) and compared with that from healthy donors (HD). The frequency of IFN-γ-producing T cells in response to peptide pools covering immunogenic regions of structural and nonstructural ZIKV proteins was quantified using an ELISpot assay. Results: Circulating CD4+ and CD8+ T lymphocytes from ZIKV-infected patients expressed higher levels of IFN-γ and pSTAT-5, as well as cell surface markers associated with proliferation (Ki-67), activation ((HLA-DR, CD38) or exhaustion (PD1 and CTLA-4), compared to those from HD. Activation of CD4+ and CD8+ memory T cell subsets, including Transitional Memory T Cells (TTM), Effector Memory T cells (TEM), and Effector Memory T cells Re-expressing CD45RA (TEMRA), was prominent among CD4+ T cell subset of ZIKV-infected patients and was associated with increased levels of IFN-γ, pSTAT-5, Ki-67, CTLA-4, and PD1, as compared to HD. Additionally, approximately 30% of ZIKV-infected patients exhibited a T cell response primarily directed against the ZIKV NS5 protein. Conclusion: Circulating T lymphocytes spontaneously produce IFN-γ and express elevated levels of pSTAT-5 during the early phase of ZIKV infection whereas recognition of ZIKV antigen results in the generation of virus-specific IFN-γ-producing T cells. [ABSTRACT FROM AUTHOR]

In the monitoring of human Toxoplasma gondii infection, it is crucial to confirm the development of a specific Th1/Th17 immune response memory. The use of a simple, specific, and sensitive assay to follow the T-cell activation is thus required. Current protocols are not always specific as stimulation with peptides is Human Leukocyte Antigen (HLA)-dependent, while stimulation with total-lysis antigens tends to stimulate seronegative donors resulting to false positives. Here, an improved ELISPOT protocol is reported, using peripheral blood mononuclear cells (PBMC) of T.gondii-infected donors, incubated with the inactivated parasite. The results showed that, contrary to standard protocols, a pre-incubation step at high cell density in presence of the inactivated parasite allowed a specific Th1/Th17 response with the secretion of IFN-γ, IL-2, IL-12 and IL-17 cytokines. This protocol allows to evaluate precisely the immune response after a T.gondii infection. [ABSTRACT FROM AUTHOR]

Background: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity. Results: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1β, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity. Conclusions: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care. [ABSTRACT FROM AUTHOR]

Background: The treatment response to corticosteroids in patients with sarcoidosis is highly variable. CD4+ T cells are central in sarcoid pathogenesis and their phenotype in peripheral blood (PB) associates with disease course. We hypothesized that the phenotype of circulating T cells in patients with sarcoidosis may correlate with the response to prednisone treatment. Therefore, we aimed to correlate frequencies and phenotypes of circulating T cells at baseline with the pulmonary function response at 3 and 12 months during prednisone treatment in patients with pulmonary sarcoidosis. Methods: We used multi-color flow cytometry to quantify activation marker expression on PB T cell populations in 22 treatment-naïve patients and 21 healthy controls (HCs). Pulmonary function tests at baseline, 3 and 12 months were used to measure treatment effect. Results: Patients with sarcoidosis showed an absolute forced vital capacity (FVC) increase of 14.2% predicted (± 10.6, p < 0.0001) between baseline and 3 months. Good response to prednisone (defined as absolute FVC increase of ≥ 10% predicted) was observed in 12 patients. CD4+ memory T cells and regulatory T cells from patients with sarcoidosis displayed an aberrant phenotype at baseline, compared to HCs. Good responders at 3 months had significantly increased baseline proportions of PD-1+CD4+ memory T cells and PD-1+ regulatory T cells, compared to poor responders and HCs. Moreover, decreased fractions of CD25+ cells and increased fractions of PD-1+ cells within the CD4+ memory T cell population correlated with ≥ 10% FVC increase at 12 months. During treatment, the aberrantly activated phenotype of memory and regulatory T cells reversed. Conclusions: Increased proportions of circulating PD-1+CD4+ memory T cells and PD-1+ regulatory T cells and decreased proportions of CD25+CD4+ memory T cells associate with good FVC response to prednisone in pulmonary sarcoidosis, representing promising new blood biomarkers for prednisone efficacy. Trial registration: NL44805.078.13 [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the most common cancer in females. The immune system has a crucial role in the fight against cancer. B and T cells, the two main components of the adaptive immunity, are critical players that specifically target tumor cells. However, B cells, in contrast to T cells, and their role in cancer inhibition or progression is less investigated. Accordingly, in this study, we assessed and compared the frequency of naïve and different subsets of memory B cells in the peripheral blood of patients with breast cancer and healthy women. Results: We found no significant differences in the frequencies of peripheral CD19+ B cells between the patients and controls. However, there was a significant decrease in the frequency of CD19+IgM+ B cells in patients compared to the control group (P=0.030). Moreover, the patients exhibited higher percentages of atypical memory B cells (CD19+CD27‒IgM‒, P=0.006) and a non-significant increasing trend in switched memory B cells (CD19+CD27+IgM‒, P=0.074). Further analysis revealed a higher frequency of atypical memory B cells (aMBCs) in the peripheral blood of patients without lymph node involvement as well as those with a tumor size greater than 2cm or with estrogen receptor (ER) negative/progesterone receptor (PR) negative tumors, compared with controls (P=0.030, P=0.040, P=0.031 and P=0.054, respectively). Conclusion: Atypical memory B cells (CD19+CD27‒IgM‒) showed a significant increase in the peripheral blood of patients with breast cancer compared to the control group. This increase seems to be associated with tumor characteristics. Nevertheless, additional research is necessary to determine the precise role of these cells during breast cancer progression [ABSTRACT FROM AUTHOR]

Inborn errors of immunity are a group of rare genetically determined diseases that impair immune system development or function. Many of these diseases include immune dysregulation, autoimmunity, or autoinflammation as prominent clinical features. In some children diagnosed with very early onset inflammatory bowel disease (VEOIBD), monogenic inborn errors of immune dysregulation underlie disease. We report a case of VEOIBD caused by a novel homozygous loss of function mutation in IL10RB. We use cytometry by time-of-flight with a broad panel of antibodies to interrogate the immunophenotype of this patient and detect reduced frequencies of CD4 and CD8 T cells with additional defects in some populations of T helper cells, innate-like T cells, and memory B cells. Finally, we identify the patient's mutation as a founder allele in an isolated indigenous population and estimate the age of this variant by studying the shared ancestral haplotype. A novel homozygous mutation in IL10RB causing neonatal onset inflammatory bowel disease was identified. This mutation caused a complete loss of IL-10-dependent signaling and this patient showed aberrant frequencies of some B- and T-cell subsets. This mutation resulted from a founder effect in a small and relatively isolated indigenous population. [ABSTRACT FROM AUTHOR]

Esophageal cancer (ESCA) has a bad prognosis. Long non-coding RNA (lncRNA) impacts on cell proliferation. However, the prognosis function of N6-methyladenosine (m6A)-associated lncRNAs (m6A-lncRNAs) in ESCA remains unknown. Univariate Cox analysis was applied to investigate prognosis related m6A-lncRNAs, based on which the samples were clustered. Wilcoxon rank and Chi-square tests were adopted to compare the clinical traits, survival, pathway activity and immune infiltration in different clusters where overall survival, clinical traits (N stage), tumor-invasive immune cells and pathway activity were found significantly different. Through least absolute shrinkage and selection operator and proportional hazard (Lasso-Cox) model, five m6A-lncRNAs were selected to construct the prognostic signature (m6A-lncSig) and risk score. To investigate the link between risk score and clinical traits or immunological microenvironments, Chi-square test and Spearman correlation analysis were utilized. Risk score was found connected with N stage, tumor stage, different clusters, macrophages M2, B cells naive and T cells CD4 memory resting. Risk score and tumor stage were found as independent prognostic variables. And the constructed nomogram model had high accuracy in predicting prognosis. The obtained m6A-lncSig could be taken as potential prognostic biomarker for ESCA patients. This study offers a theoretical foundation for clinical diagnosis and prognosis of ESCA. [ABSTRACT FROM AUTHOR]

Macrophages are key regulators in bone repair and regeneration. Recent studies have shown that long-term epigenetic changes and metabolic shifts occur during specific immune training of macrophages that affect their functional state, resulting in heightened (trained) or reduced (tolerant) responses upon exposure to a second stimulus. This is known as innate immune memory. Here, we study the impact of macrophages' memory trait on osteoblast differentiation of human mesenchymal stromal cells (hMSCs) and osteoclast differentiation. An in vitro trained immunity protocol of monocyte-derived macrophages was employed using inactivated Candida albicans and Bacillus Calmette–Guérin (BCG) to induce a 'trained' state and Pam3CSK4 (PAM) and Lipopolysaccharides (LPS) to induce a 'tolerance' state. Macrophages were subsequently cocultured with hMSCs undergoing osteogenic differentiation during either resting (unstimulated) or inflammatory conditions (restimulated with LPS). Alkaline phosphatase activity, mineralization, and cytokine levels (TNF, IL-6, oncostatin M and SDF-1α) were measured. In addition, macrophages underwent osteoclast differentiation. Our findings show that trained and tolerized macrophages induced opposing results. Under resting conditions, BCG-trained macrophages enhanced ALP levels (threefold), while under inflammatory conditions this was found in the LPS-tolerized macrophages (fourfold). Coculture of hMSCs with trained macrophages showed mineralization while tolerized macrophages inhibited the process under both resting and inflammatory conditions. While osteoclast differentiation was not affected in trained-macrophages, this ability was significantly loss in tolerized ones. This study further confirms the intricate cross talk between immune cells and bone cells, highlighting the need to consider this interaction in the development of personalized approaches for bone regenerative medicine. [ABSTRACT FROM AUTHOR]

Core homeostatic and activation signatures have been defined for mammalian microglia in new transcriptomic and functional studies. Microglia respond to changes in the homeostatic environment using similar signal modules during neurodevelopment as those seen for different types of neurodegenerative diseases. Danger signals present in neurodevelopment often mirror those encountered by microglia in neurodegenerative conditions. The mechanisms microglia utilize to sense their environment (sensome) are akin to those defined in other tissue-resident macrophage populations. Convergent versus divergent responses among microglia might reflect differences in expressed/engaged receptors, microenvironment, and immunological memory. Interest in microglia is surging with increased recognition that these cells significantly influence brain function and neurologic disease pathogenesis. When aiming to treat different neurologic diseases, a fine-tuned approach to enhance the protective abilities of microglia while dampening destructive off-target effects is an attractive and compelling one. Understanding the receptors, downstream signaling, and functional outputs that microglia employ throughout a healthy lifespan and in diverse disease states (their toolkit) is essential for harnessing their therapeutic potential. After decades of being overlooked, a recent wave of studies have explored the roles of microglia in brain health and disease. Microglia perform important physiological functions to set up and maintain proper neural network functions, as well as orchestrate responses to toxic stimuli to limit harm. Many microglial transcriptional programs, extracellular sensing molecules, and functional outputs are seen throughout life. A stark example is the similarity of microglial responses to stressors during neurodevelopment and neurodegeneration. The same themes often match that of other tissue-resident macrophages, presenting an opportunity to apply known concepts as therapeutics develop. We argue that microglial signaling during development and neurologic disease overlap with one another and with other tissue-resident macrophage pathways, in part due to similar sensed stimuli and a conserved sensome of receptors and signaling molecules, akin to a toolkit. [ABSTRACT FROM AUTHOR]

Off-the-shelf immunotherapeutics that suppress tumor growth and provide durable protection against relapse could enhance cancer treatment. We report preclinical studies on a CD33 x CD3 bivalent bispecific diabody, AMV564, that not only suppresses tumor growth, but also facilitates memory responses in a mouse model of acute myelogenous leukemia (AML). Mechanistically, a single 5-day treatment with AMV564 seems to reduce tumor burden by redirection of T cells, providing a time window for allogeneic or other T cells that innately recognize tumor antigens to become activated and proliferate. When the concentration of bispecific becomes negligible, the effector: target ratio has also shifted, and these activated T cells mediate long-term tumor control. To test the efficacy of AMV564 in vivo, we generated a CD33+ MOLM13CG bioluminescent human cell line and optimized conditions needed to control these cells for 62 days in vivo in NSG mice. Of note, not only did MOLM13CG become undetectable by bioluminescence imaging in response to infusion of human T cells plus AMV564, but also NSG mice that had cleared the tumor also resisted rechallenge with MOLM13CG in spite of no additional AMV564 treatment. In these mice, we identified effector and effector memory human CD4+ and CD8+ T cells in the peripheral blood immediately prior to rechallenge that expanded significantly during the subsequent 18 days. In addition to the anti-tumor effects of AMV564 on the clearance of MOLM13CG cells in vivo, similar effects were seen when primary CD33+ human AML cells were engrafted in NSG mice even when the human T cells made up only 2% of the peripheral blood cells and AML cells made up 98%. These studies suggest that AMV564 is a novel and effective bispecific diabody for the targeting of CD33+ AML that may provide long-term survival advantages in the clinic. [ABSTRACT FROM AUTHOR]

Summary: Innate immune memory endows innate immune cells with antigen independent heightened responsiveness to subsequent challenges. The durability of this response can be mediated by inflammation induced epigenetic and metabolic reprogramming in hematopoietic stem and progenitor cells (HSPCs) that are maintained through differentiation to mature immune progeny. Understanding the mechanisms and extent of trained immunity induction by pathogens and vaccines, such as BCG, in HSPC remains a critical area of exploration with important implications for health and disease. Here we review these concepts and present new analysis to highlight how inflammatory reprogramming of HSPC can potently alter immune tone, including to enhance specific anti‐tumor responses. New findings in the field pave the way for novel HSPC targeting therapeutic strategies in cancer and other contexts of immune modulation. Future studies are expected to unravel diverse and extensive effects of infections, vaccines, microbiota, and sterile inflammation on hematopoietic progenitor cells and begin to illuminate the broad spectrum of immunologic tuning that can be established through altering HSPC phenotypes. The purpose of this review is to draw attention to emerging and speculative topics in this field where we posit that focused study of HSPC in the framework of trained immunity holds significant promise. [ABSTRACT FROM AUTHOR]

Summary: Conventionally, it was thought that innate immunity operated through a simple system of nonspecific responses to an insult. However, this perspective now seems overly simplistic. It has become evident that intricate cooperation and networking among various cells, receptors, signaling pathways, and protein complexes are essential for regulating and defining the overall activation status of the immune response, where the distinction between innate and adaptive immunity becomes ambiguous. Given the evolutionary timeline of vertebrates and the success of plants and invertebrates which depend solely on innate immunity, immune memory cannot be considered an innovation of only the lymphoid lineage. Indeed, the evolutionary innate immune memory program is a conserved mechanism whereby innate immune cells can induce a heightened response to a secondary stimulus due to metabolic and epigenetic reprogramming. Importantly, the longevity of this memory phenotype can be attributed to the reprogramming of self‐renewing hematopoietic stem cells (HSCs) in the bone marrow, which is subsequently transmitted to lineage‐committed innate immune cells. HSCs reside within a complex regulated network of immune and stromal cells that govern their two primary functions: self‐renewal and differentiation. In this review, we delve into the emerging cellular and molecular mechanisms as well as metabolic pathways of innate memory in HSCs, which harbor substantial therapeutic promise. [ABSTRACT FROM AUTHOR]

Summary: Group 3 innate lymphoid cells (ILC3s) are tissue‐resident immune lymphocytes that critically regulate intestinal homeostasis, organogenesis, and immunity. ILC3s possess the capacity to "sense" the inflammatory environment within tissues, especially in the context of pathogen challenges that imprints durable non‐antigen‐specific changes in ILC3 function. As such, ILC3s become a new actor in the emerging field of trained innate immunity. Here, we summarize recent discoveries regarding ILC3 responses to bacterial challenges and the role these encounters play in triggering trained innate immunity. We further discuss how signaling events throughout ILC3 ontogeny potentially control the development and function of trained ILC3s. Finally, we highlight the open questions surrounding ILC3 "training" the answers to which may reveal new insights into innate immunity. Understanding the fundamental concepts behind trained innate immunity could potentially lead to the development of new strategies for improving immunity‐based modulation therapies for inflammation, infectious diseases, and cancer. [ABSTRACT FROM AUTHOR]

Summary: Over the past decade, compelling evidence has unveiled previously overlooked adaptive characteristics of innate immune cells. Beyond their traditional role in providing short, non‐specific protection against pathogens, innate immune cells can acquire antigen‐agnostic memory, exhibiting increased responsiveness to secondary stimulation. This long‐term de‐facto innate immune memory, also termed trained immunity, is mediated through extensive metabolic rewiring and epigenetic modifications. While the upregulation of trained immunity proves advantageous in countering immune paralysis, its overactivation contributes to the pathogenesis of autoinflammatory and autoimmune disorders. In this review, we present the latest advancements in the field of innate immune memory followed by a description of the fundamental mechanisms underpinning trained immunity generation and different cell types that mediate it. Furthermore, we explore its implications for various diseases and examine current limitations and its potential therapeutic targeting in immune‐related disorders. [ABSTRACT FROM AUTHOR]

Summary: Clonal expansion of antigen‐specific lymphocytes is the fundamental mechanism enabling potent adaptive immune responses and the generation of immune memory. Accompanied by pronounced epigenetic remodeling, the massive proliferation of individual cells generates a critical mass of effectors for the control of acute infections, as well as a pool of memory cells protecting against future pathogen encounters. Classically associated with the adaptive immune system, recent work has demonstrated that innate immune memory to human cytomegalovirus (CMV) infection is stably maintained as large clonal expansions of natural killer (NK) cells, raising questions on the mechanisms for clonal selection and expansion in the absence of re‐arranged antigen receptors. Here, we discuss clonal NK cell memory in the context of the mechanisms underlying clonal competition of adaptive lymphocytes and propose alternative selection mechanisms that might decide on the clonal success of their innate counterparts. We propose that the integration of external cues with cell‐intrinsic sources of heterogeneity, such as variegated receptor expression, transcriptional states, and somatic variants, compose a bottleneck for clonal selection, contributing to the large size of memory NK cell clones. [ABSTRACT FROM AUTHOR]

Summary: Group 2 Innate Lymphoid Cells (ILC2s) are innate lymphocytes involved in type 2 immunity. ILC2s are abundant at the barrier tissues and upon allergen exposure, respond to epithelial‐derived alarmins by producing type 2 cytokines (e.g., IL‐5 and IL‐13). Upon activation, some of these activated ILC2s acquire immunological memory and can mount enhanced responses upon further allergen encounters. Here, we review recent findings of the cellular and molecular mechanisms underlying immune memory in ILC2s both in mice and humans and discuss the implications of memory ILC2s in the context of allergic diseases. [ABSTRACT FROM AUTHOR]

Background: The gut is an important site for human immunodeficiency virus (HIV) infection and immune responses. The role of gut mucosal immune cells in immune restoration in patients infected with HIV undergoing antiretroviral therapy remains unclear. Methods: Ileocytes, including 54 475 immune cells, were obtained from colonoscopic biopsies of five HIV‐negative controls, nine immunological responders (IRs), and three immunological non‐responders (INRs) and were analyzed using single‐cell RNA sequencing. Immunohistochemical assays were performed for validation. The 16S rRNA gene was amplified using PCR in faecal samples to analyze faecal microbiota. Flow cytometry was used to analyze CD4+ T‐cell counts and the activation of T cells. Results: This study presents a global transcriptomic profile of the gut mucosal immune cells in patients infected with HIV. Compared with the IRs, the INRs exhibited a lower proportion of gut plasma cells, especially the IGKC+IgA+ plasma cell subpopulation. IGKC+IgA+ plasma cells were negatively associated with enriched f. Prevotellaceae the INRs and negatively correlated with the overactivation of T cells, but they were positively correlated with CD4+ T‐cell counts. The INRs exhibited a higher proportion of B cells than the IRs. Follicular and memory B cells were significantly higher in the INRs. Reduced potential was observed in the differentiation of follicular or memory B cells into gut plasma cells in INRs. In addition, the receptor‐ligand pairs CD74_MIF and CD74_COPA of memory B/ follicular helper T cells were significantly reduced in the INRs, which may hinder the differentiation of memory and follicular B cells into plasma cells. Conclusions: Our study shows that plasma cells are dysregulated in INRs and provides an extensive resource for deciphering the immune pathogenesis of HIV in INRs. Key points: An investigation was carried out at the single‐cell‐level to analyze gut mucosal immune cells alterations in PLWH after ART.B cells were significantly increased and plasma cells were significantly decreased in the INRs compared to the IRs and NCs.There are gaps in the transition from gut follicular or memory B cellsinto plasma cells in INRs. [ABSTRACT FROM AUTHOR]

In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease. This Review discusses joint-specific memory (the tendency of arthritis to recur in previously inflamed joints), explores the involvement of resident memory T cells and other contributors, and evaluates how arthritis might spread to new joints, emphasizing the important of sustained treatment. Key points: In rheumatoid arthritis and juvenile idiopathic arthritis, joints previously affected are more likely to flare than joints previously spared, a phenomenon termed joint-specific memory. One mechanism underlying joint-specific memory is the accumulation of synovial resident memory T (TRM) cells, long-lived resident lymphocytes that remain during remission and promote recurrent disease. Synovial TRM cells are predominantly CD8+ T cells and exhibit a restricted TCR repertoire; in animal models, TRM cells trigged by specific antigens induce arthritis flare by releasing chemokines, including CCL5. Mechanisms that predispose individual joints to greater disease activity include inflammation-induced fibroblast priming and an increase in the abundance of pro-inflammatory macrophages compared with that of regulatory macrophages. Recognition that both systemic factors and local factors drive arthritis suggests a new paradigm of chronicity, the joint accumulation model, implying a 'rolling window of opportunity' for therapy, even in established arthritis. [ABSTRACT FROM AUTHOR]