Search

This paper investigates dynamical behaviors of the tumor-immune system perturbed by environmental noise. The model describes the response of the cytotoxic T lymphocyte to the growth of an immunogenic tumor. The main methods are stochastic Lyapunov analysis, comparison theorem for stochastic differential equations (SDEs), and strong ergodicity theorem. Firstly, we prove the existence and uniqueness of the global positive solution for the tumor-immune system. Then we go a further step to study the boundaries of moments for tumor cells and effector cells and the asymptotic behavior in the boundary equilibrium points. Furthermore, we discuss the existence and uniqueness of stationary distribution and stochastic permanence of the tumor-immune system. Finally, we give several examples and numerical simulations to verify our results. [ABSTRACT FROM AUTHOR]

Caspase-3 is generally considered to be the most important terminal shear enzyme in the process of apoptosis, as well as an important part of cytotoxic T lymphocytes (CTL) killing mechanism, which is confirmed to play an important role in vertebrate cell apoptosis and immune system, and is poorly reported in invertebrates. In this paper, we used bioinformatics to perform amino acid multiple sequence alignment and protein structural domain analysis, and constructed a phylogenetic tree to identify the full-length cDNA of the cloned caspase-3 of Cristaria plicata (Named CpCaspase-3). The expression of caspase-1, caspase-7, caspase-8, and caspase-9 was found to be down-regulated by double-stranded RNA interference of CpCaspase-3 in C. plicata. Some degree of disruption of the caspase signaling pathway occurs. The expression of CpCaspase-3 was affected after injection of Lipopolysaccharide (LPS), Peptidoglycan (PGN), polyinosinic-polycytidylic acid (poly(I:C)), and Aeromonas hydrophila. These results were suggested that CpCaspase-3 was involved in the immune response of C. plicata. The wound recovery process of C. plicata was simulated and CpCaspase-3 was found to promote wound recovery. An autophagy inhibition and autophagy activation model of mussels was constructed, where apoptosis and autophagy undergo crosstalk, and inhibition of autophagy induces the onset of apoptosis, and similarly autophagy activation inhibits the process of apoptosis instead. In addition, a recombinant CpCaspase-3-pEGFP-C1 plasmid was constructed for subcellular localization experiments and found that CpCaspase-3 was distributed in both the nucleus and the cytoplasm. This paper aims to unveil the immune mechanism of C. plicata and provide a theoretical basis for the healthy culture of shellfish. • It was demonstrated that CpCaspase-3 plays a key role in the wound healing process of Cristaria plicata. • A negative correlation between autophagy and apoptosis in the Cristaria plicata was revealed. • It was revealed that microcystin increased the complexity of the crosstalk between autophagy and apoptosis. [ABSTRACT FROM AUTHOR]

Background:. CD8+ Cytotoxic T lymphocytes play a key role in the pathogenesis of autoimmune diseases and clinical conditions such as graft versus host disease and graft rejection. Mesenchymal Stromal Cells (MSCs) are multipotent cells with tissue repair and immunomodulatory capabilities. Since they are able to suppress multiple pathogenic immune responses, MSCs have been proposed as a cellular therapy for the treatment of immune-mediated diseases. However, the mechanisms underlying their immunosuppressive properties are not yet fully understood. MSCs have the remarkable ability to sense tissue injury and inflammation and respond by donating their own mitochondria to neighboring cells. Whether mitochondrial transfer has any role in the repression of CD8+ responses is unknown. Methods and results:. We have utilized CD8+ T cells from Clone 4 TCR transgenic mice that differentiate into effector cells upon activation in vitro and in vivo to address this question. Allogeneic bone marrow derived MSCs, co-cultured with activated Clone 4 CD8+ T cells, decreased their expansion, the production of the effector cytokine IFNγ and their diabetogenic potential in vivo. Notably, we found that during this interaction leading to suppression, MSCs transferred mitochondria to CD8+ T cells as evidenced by FACS and confocal microscopy. Transfer of MSC mitochondria to Clone 4 CD8+ T cells also resulted in decreased expansion and production of IFNγ upon activation. These effects overlapped and were additive with those of prostaglandin E2 secreted by MSCs. Furthermore, preventing mitochondrial transfer in co-cultures diminished the ability of MSCs to inhibit IFNγ production. Finally, we demonstrated that both MSCs and MSC mitochondria downregulated T-bet and Eomes expression, key transcription factors for CTL differentiation, on activated CD8+ T cells. Conclusion:. In this report we showed that MSCs are able to interact with CD8+ T cells and transfer them their mitochondria. Mitochondrial transfer contributed to the global suppressive effect of MSCs on CD8+ T cell activation by downregulating T-bet and Eomes expression resulting in impaired IFNγ production of activated CD8+ T cells. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor-T cell (CAR-T) therapy has transformed the management of refractory hematological malignancies. Now that targeting pathogenic cells of interest with antigen-directed cytotoxic T lymphocytes is possible, the field is expanding the reach of CAR-T therapy beyond oncology. Recently, breakthrough progress has been made in the application of CAR-T technology to autoimmune diseases, exploiting the same validated targets that were used by pioneering CAR-T therapies in hematology. Here, we discuss recent advances and outcomes that are paving the way for extension to new therapeutic areas, including autoimmunity. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic autoimmune condition characterized by hyperglycemia resulting from the destruction of insulin-producing β-cells that is traditionally deemed irreversible, but partial remission (PR) with temporary reversal of hyperglycemia is sometimes observed. Here we use single-cell RNA sequencing to delineate the immune cell landscape across patients in different T1D stages. Together with cohort validation and functional assays, we observe dynamic changes in TIGIT+CCR7− Tregs and CD226+CCR7−CD8+ cytotoxic T cells during the peri-remission phase. Machine learning algorithms further identify TIGIT+CCR7− Tregs and CD226+CD8+ T cells as biomarkers for β-cell function decline in a predictive model, while cell communication analysis and in vitro assays suggest that TIGIT+CCR7− Tregs may inhibit CD226+CCR7−CD8+ T cells via TGF-β signaling. Lastly, in both cyclophosphamide-induced and streptozotocin (STZ)-induced mouse diabetes models, CD226 inhibition postpones insulitis onset and reduces hyperglycemia severity. Our results thus identify two interrelated immune cell subsets that may serve as biomarkers for monitoring disease progression and targets for therapeutic intervention of T1D. Type 1 diabetes (T1D) manifests as hyperglycemia, with spontaneous remission occasionally observed, but the underneath mechanisms are unclear. Here the authors analyses patients at different stages to find two populations of immune cells correlating with disease progression or remission, while results from mouse diabetes models validate these observations. [ABSTRACT FROM AUTHOR]

NKG2D is a central activating receptor involved in target recognition and killing by Natural Killer and CD8+ T cells. The known role of NKG2D is to recognize a family of self-induced stress ligands that are upregulated on stressed cells such as cancerous or virally infected cells. Fungal pathogens are a major threat to human health, infecting more than a billion patients yearly and becoming more common and drug resistant. Here we show that NKG2D plays a critical role in the immune response against fungal infections. NKG2D can recognize fungal pathogens from most major families including Candida, Cryptococcus and Aspergillus species, and mice lacking NKG2D are extremely sensitive to fungal infections in models of both invasive and mucosal infections, making NKG2D an anti-fungal pattern recognition receptor. NKG2D is a central activating receptor know to recognise stress ligangs upregulated during cancer or infection. Here, Charpak-Amikam et al show that NKG2D also recognises fungal pathogens and plays a critical role in mounting an appropriate immune response to them. [ABSTRACT FROM AUTHOR]

Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors. Immune evasion is a feature of HPV-positive head and neck squamous cell carcinoma (HNSCC). Here the authors report that a circular RNA, circE7, encoded by HPV promotes immune evasion in HNSCC by promoting downregulation of galectin-9. [ABSTRACT FROM AUTHOR]

Recent research has focused on immunotherapy with no side effects as an innovative medical treatment for cancer. However, typical drugs for immunotherapy are very expensive. Here, we propose the use of immunoceramics that activate immune cells by contact with their surface. Previous studies demonstrated that polymers, including the phenylboronic acid group, could activate lymphocytes. This activation may be due to the interaction between the sugar chains in cells and the OH group in B(OH)3 formed via the dissociation of the BO2 group. We have clarified that boron-containing apatite (BAp) activated lymphocytes in vitro. In this study, we fabricated the ceramic surfaces using the CaO-P2O5-SiO2-B2O3 system (CPSB ceramics) containing BAp as a main crystalline phase. The results of the in vitro evaluation indicated that killer T cells in splenocytes cocultured with the CPSB ceramics were more numerous than in splenocytes cocultured on a control surface. The results of the in vivo evaluation indicated that the CPSB ceramics significantly inhibited tumor growth when CD8-positive T cells were cultured on individual ceramics and subsequently injected into tumor-bearing mice. The present CPSB ceramics are expected to be a valuable biomaterial for immunotherapy. [ABSTRACT FROM AUTHOR]

Mathematical analysis of epidemics is crucial for long‐term disease prediction and helps to guide decision‐makers in terms of public health policy. In this study, we develop a within‐host mathematical model of the malaria parasite dynamics with the effect of an adaptive immune response. The model includes six compartments, namely, the uninfected red blood cells, infected red blood cells, merozoites, gametocytes, cytotoxic T cells immune response, and antibodies immune response, which are activated in the host to attack the parasite. We establish the well‐posedness and biological feasibility of the model in terms of proving the non‐negativity and boundedness of solutions. The most important threshold value in the epidemiological model known as the basic reproduction number, R0, which is used to determine the stability of the steady state, is investigated. Furthermore, the parasite‐free equilibrium is locally and globally stable if the basic reproduction number, R0<1, otherwise, if R0>1, then there exist four parasite‐persistence equilibria. The stability conditions of these parasite‐persistence equilibria are presented. Sensitivity analysis of the basic reproduction number shows that parameters representing the recruitment rate of uninfected red blood cells, infection rate of red blood cells by merozoites, and the average number of merozoites per ruptured infected red blood cells are the most influential ones in affecting the dynamics. Finally, several numerical simulations of the model are presented to supplement the theoretical and analytical findings. It has been observed that numerical simulations and theoretical results are coherent. The response of cytotoxic T cells and antibodies has a significant impact on suppressing infected cells and malaria parasites in the host's body. [ABSTRACT FROM AUTHOR]

Stevia rebaudiana Bertoni, which is a medicinal plant used in the treatment of diabetes, was the focus of this study aiming to investigate its immunomodulatory properties in diabetes. To form the diabetes group, rats were injected intraperitoneally with STZ and rats with blood glucose levels above 200 mg/dL 2 days after STZ injection were included in the diabetes group. To form the stevia and diabetes + stevia groups, stevia was administered daily by gavage to both healthy and diabetic rats for 28 days. At the end of 28 days, the levels of interleukin‐1 beta and tumor necrosis factor‐alpha in the blood were measured by ELISA. CD3, CD4, and CD8 protein levels in the blood were determined by flow cytometry. Rat body weight increased in the diabetes +25 mg/kg bW stevia group compared with the diabetes group. Blood glucose levels were significantly decreased in the diabetes +25 mg/kg bW stevia group compared to the diabetes group (**p <.01). IL‐1β cytokine levels decreased significantly in the diabetes +25 mg/kg bW stevia group compared to the diabetes group (**p <.01). TNF‐α cytokine levels decreased significantly in the diabetes +25 mg/kg bW stevia group compared to the diabetes group (**p <.01). The amount of CD8 + T cells decreased significantly in the diabetes +25 mg/kg bW stevia group compared to the diabetes group (*p <.05). The stevia diet leads to a reduction in peripheral circulating cytotoxic T cells and proinflammatory cytokines interleukin‐1 beta and tumor necrosis factor‐alpha under hyperglycemic conditions. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) greatly contribute to immune checkpoint inhibitor (ICI) resistance of cancer. However, its underlying mechanisms and whether TAMs can be promising targets to overcome ICI resistance remain to be unveiled. Through integrative analysis of immune multiomics data and single‐cell RNA‐seq data (iMOS) in lung adenocarcinoma (LUAD), lymphotoxin β receptor (LTBR) is identified as a potential immune checkpoint of TAMs, whose high expression, duplication, and low methylation are correlated with unfavorable prognosis. Immunofluorescence staining shows that the infiltration of LTBR+ TAMs is associated with LUAD stages, immunotherapy failure, and poor prognosis. Mechanistically, LTΒR maintains immunosuppressive activity and M2 phenotype of TAMs by noncanonical nuclear factor kappa B and Wnt/β‐catenin signaling pathways. Macrophage‐specific knockout of LTBR hinders tumor growth and prolongs survival time via blocking TAM immunosuppressive activity and M2 phenotype. Moreover, TAM‐targeted delivery of LTΒR small interfering RNA improves the therapeutic effect of ICI via reversing TAM‐mediated immunosuppression, such as boosting cytotoxic CD8+ T cells and inhibiting granulocytic myeloid‐derived suppressor cells infiltration. Taken together, we bring forth an immune checkpoint discovery pipeline iMOS, identify LTBR as a novel immune checkpoint of TAMs, and propose a new immunotherapy strategy by targeting LTBR+ TAMs. Highlights: Integrative analysis of immune multiomics data and single‐cell RNA‐seq data pipeline is developed and finds lymphotoxin β receptor (LTBR) expression specific in tumor‐associated macrophages (TAMs).LTΒR+ TAMs correlate with lung adenocarcinoma stages, immunotherapy resistance, and prognosis.LTΒR maintains TAM immunosuppressive activity and M2 phenotype by noncanonical nuclear factor kappa B signaling and Wnt/β‐catenin signaling.Disruption of LTΒR in TAMs enhances the therapeutic effect of cancer immunotherapy. [ABSTRACT FROM AUTHOR]

The global incidence of cutaneous squamous cell carcinoma (cSCC), a prevalent and aggressive skin cancer, has risen significantly, posing a substantial public health challenge. This study investigates the tumor microenvironment (TME) of cSCC by focusing on the spatial distribution patterns of immune and vascular markers (CD31, CD20, CD4, and CD8) using fractal dimension (FD) analysis. Our analysis encompassed 141 cases, including 100 invasive cSCCs and 41 specimens with pre-invasive lesions exclusively, and the rest were peripheral pre-invasive lesions from the invasive cSCC class. The FD values for each marker were computed and compared between pre-invasive and invasive lesion classes. The results revealed significant differences in FD values between the two classes for CD20 and CD31 markers, suggesting distinct alterations in B cell distribution and angiogenic activity during cSCC progression. However, CD4 and CD8 markers did not exhibit significant changes individually. Still, the CD4/CD8 ratio showed a significant difference, suggesting a potential shift in the balance between T helper and cytotoxic T cell responses, impacting the immune landscape as lesions progressed from pre-invasive to invasive stages. These findings underscore the complexity and heterogeneity of the TME in cSCC and highlight the potential of FD analysis as a quantitative tool for characterizing tumor progression. Further research is needed to elucidate the implications of these differences in the clinical management of cSCC. [ABSTRACT FROM AUTHOR]

Purpose: Gastric cancer exhibits molecular heterogeneity, with the microsatellite instability–high (MSI-H) subtype drawing attention for its distinct features. Despite a higher survival rate, MSI-H gastric cancer lack significant benefits from conventional chemotherapy. The immune checkpoint inhibitors, presents a potential avenue, but a deeper understanding of the tumor immune microenvironment of MSI-H gastric cancer is essential. Materials and Methods: We explored the molecular characteristics of CD8+ T-cell subtypes in three MSI-H and three microsatellite stable (MSS) gastric cancer samples using single-cell RNA sequencing and spatial transcriptome analysis. Results: In MSI-H gastric cancer, significantly higher proportions of effector memory T cell (Tem), exhausted T cell (Tex), proliferative exhausted T cell (pTex), and proliferative T cell were observed, while MSS gastric cancer exhibited significantly higher proportions of mucosal-associated invariant T cell and natural killer T cell. In MSI-H gastric cancer, Tex and pTex exhibited a significant upregulation of the exhaustion marker LAG3, as well as elevated expression of effector function markers such as IFNG, GZMB, GZMH, and GZMK, compared to those in MSS gastric cancer. The interferon γ (IFN-γ) signaling pathway of Tex and pTex was retained compared to those of MSS gastric cancer. The spatial transcriptome analysis demonstrates the IFN-γ signaling pathway between neighboring Tex and malignant cell, showcasing a significantly elevated interaction in MSI-H gastric cancer. Conclusion: Our study reveals novel finding indicating that IFN-γ signaling pathway is retained in Tex and pTex of MSI-H gastric cancer, offering a comprehensive perspective for future investigations into immunotherapy for gastric cancer. [ABSTRACT FROM AUTHOR]

Introduction: In this study, we report a novel therapeutic approach redirecting antigen-specific CD4+ T cells recognizing a hybrid insulin peptide (BDC2.5 T cell receptor (TCR) transgenic CD4+ T cells) to attract and suppress islet-specific CD8+ T cells T cells in the non-obese diabetic (NOD) mouse model, and prevent the development of autoimmune diabetes. Methods: Purified BDC2.5 CD4+ T cells were induced to differentiate into regulatory T cells (Tregs). The Tregs were then electroporated with mRNA encoding chimeric human β2 microglobulin (hβ 2m) covalently linked to insulin B chain amino acids 15-23 (designated INS-eTreg) or islet-specific glucose-6- phosphatase related protein (IGRP) peptide 206-214 (designated IGRP-eTreg). Immunoregulatory functions of these engineered regulatory T cells (eTregs) were tested by in vitro assays and in vivo co-transfer experiments with β-cell-antigen-specific CD8+ T cells in NOD.Scid mice or by adoptive transfer into young, pre-diabetic NOD mice. Results: These eTregs were phenotyped by flow cytometry, and shown to have high expression of FoxP3, as well as other markers of Treg function, including IL- 10. They suppressed polyclonal CD4+ T cells and antigen-specific CD8+ T cells (recognizing insulin or IGRP), decreasing proliferation and increasing exhaustion and regulatory markers in vitro. In vivo, eTregs reduced diabetes development in co-transfer experiments with pathogenic antigen-specific CD8+ T cells (INS- CD8+ or IGRP-CD8+ cells) into NOD.Scid mice. Finally, when the eTreg were injected into young NOD mice, they reduced insulitis and prevented spontaneous diabetes in the recipient mice. Conclusion: Our results suggest a novel therapeutic strategy to protect NOD mice by targeting antigen-specific cytotoxic CD8+ T cells, using redirected antigen-specific CD4+ Treg cells, to suppress autoimmune diabetes. This may suggest an innovative therapy for protection of people at risk of development of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ–producing bacteria was sufficient to drive systemic tumor antigen–specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3−CD4+ and CD8+ T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ–producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease. Editor's summary: Engineering bacteria to release therapeutic candidates within tumors circumvents the severe toxicity associated with systemic delivery and is a promising strategy for immunotherapy. Li et al. engineered a strain of E. coli to express the cytokine IFN-γ within the tumor core (SLIC–IFN-γ). In mice, intratumoral injection of SLIC–IFN-γ promoted antitumor immunity by polarizing tumor-associated myeloid cells and activating cytotoxic T cells. Furthermore, SLIC–IFN-γ overcame primary resistance to PD-1 blockade by activating antigen-specific T cells and overcame acquired resistance by activating NK cells. Together, these findings suggest that SLIC–IFN-γ is an attractive therapeutic strategy to overcome resistance to PD-1 blockade. —Hannah Isles [ABSTRACT FROM AUTHOR]

After primary infection, human cytomegalovirus (HCMV) establishes lifelong persistence, underpinned by latent carriage of the virus with spontaneous reactivation events. In the immune-competent, primary infection or reactivation from latency rarely causes disease. However, HCMV can cause significant disease in immune-compromised individuals such as immune-suppressed transplant patients. Latency, where the viral genome is carried in the absence of the production of infectious virions, can be established in undifferentiated cells of the myeloid lineage. A number of stimuli can cause virus reactivation from latency to occur, beginning with the induction of viral immediate-early (IE) lytic gene expression. The suppression of viral IE gene expression to establish and maintain latent infection is known to result from a balance of viral and cellular factors. One key viral factor involved in this is the G protein-coupled receptor US28. Recently, we have shown that US28 is targeted for degradation by a modified nanobody (PCTD-Vun100bv) based on the novel PACTAC (PCSK9-antibody clearance-targeting chimeras) approach for targeted protein degradation. Furthermore, we have shown that this PCTD-Vun100bv-induced degradation of US28 results in IE gene expression in experimentally latently infected CD14+ monocytes. However, HCMV also establishes latency in CD34+ bone marrow cells, the progenitors of CD14+ cells. Here, we show that PCTD-Vun100bv also causes US28 degradation in these CD34+ primary cells, again resulting in the induction of viral IE gene expression. Additionally, we show that PCTD-Vun100bv can target US28 in naturally latently infected CD14+ monocytes from an HCMV-seropositive donor, allowing these latently infected cells to be killed by HCMV-specific cytotoxic T cells from that same donor. These observations support the view that targeting US28 for degradation during natural latency could be a tractable 'shock-and-kill' strategy to target the latent HCMV reservoir in myeloid cells. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces immune-mediated diseases. The pathophysiology of COVID-19 uses the following three mechanisms: (1) inflammasome activation mechanism; (2) cGAS–STING signaling mechanism; and (3) SAMHD1 tetramerization mechanism, which leads to IFN-I production. Interactions between the host and virus govern induction, resulting in multiorgan impacts. The NLRP3 with cGAS–STING constitutes the primary immune response. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS–STING signaling. SAMHD1 has a target motif for CDK1 to protect virion assembly, threonine 592 to modulate a catalytically active tetramer, and antiviral IFN responses to block retroviral infection. Plastic and allosteric nucleic acid binding of SAMHD1 modulates the antiretroviral activity of SAMHD1. Therefore, inflammasome activation, cGAS–STING signaling, and SAMHD1 tetramerization explain acute kidney injury, hepatic, cardiac, neurological, and gastrointestinal injury of COVID-19. It might be necessary to effectively block the pathological courses of diverse diseases. Highlights: 1. DNA-driven immune response connects with NLRP3 and controls its inflammasome activity, which leads to IFN-I production via STING. The NLRP3 with cGAS-STING constitutes the primary immune response. 2. The expression of SARS-CoV-2 ORF3a, NSP6, NSP7, and NSP8 blocks innate immune activation and facilitates virus replication by targeting the RIG-I/MDA5, TRIF, and cGAS-STING signaling. 3. Plastic and allosteric nucleic acid binding of SAMHD1 reduces the magnitude of IFN and induction of virus-specific cytotoxic T cells. SAMHD1-deficient cells detect and activate IFN-I-mediated self ISG gene expression via cGAS–STING. 4. SAMHD1 autonomously controls viral infection through innate and adaptive immunity at the level of the infected cell. [ABSTRACT FROM AUTHOR]

The development of the human immune system lasts for several years after birth. The impact of this maturation phase on the quality of adaptive immunity and the acquisition of immunological memory after infection at a young age remains incompletely defined. Here, using an antigen-reactive T cell (ARTE) assay and multidimensional flow cytometry, we profiled circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–reactive CD3+CD4+CD154+ T cells in children and adults before infection, during infection, and 11 months after infection, stratifying children into separate age groups and adults according to disease severity. During SARS-CoV-2 infection, children younger than 5 years old displayed a lower antiviral CD4+ T cell response, whereas children older than 5 years and adults with mild disease had, quantitatively and phenotypically, comparable virus-reactive CD4+ T cell responses. Adults with severe disease mounted a response characterized by higher frequencies of virus-reactive proinflammatory and cytotoxic T cells. After SARS-CoV-2 infection, preschool-age children not only maintained neutralizing SARS-CoV-2–reactive antibodies postinfection comparable to adults but also had phenotypically distinct memory T cells displaying high inflammatory features and properties associated with migration toward inflamed sites. Moreover, preschool-age children had markedly fewer circulating virus-reactive memory B cells compared with the other cohorts. Collectively, our results reveal unique facets of antiviral immunity in humans at a young age and indicate that the maturation of adaptive responses against SARS-CoV-2 toward an adult-like profile occurs in a progressive manner. Editor's summary: The immune system continues to develop throughout childhood, and it is established that children have distinct immune responses to vaccines and infections as compared with adults. Here, Manfroi et al. characterized the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children. The authors found that preschool-age children had a different adaptive immune response, with a lower frequency of antiviral CD4+ T cells, compared with older children and adults; this younger cohort also developed phenotypically distinct memory T and B cell responses after recovery compared with the other cohorts. This study highlights that responses to SARS-CoV-2 infection in young children are unique and reflect the ongoing maturation of the immune system into adulthood. —Courtney Malo [ABSTRACT FROM AUTHOR]

Tauopathies, including Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy, are characterised by the aggregation of tau into insoluble neurofibrillary tangles in the brain. Tau is subject to a range of post-translational modifications, including proteolysis, that can promote its aggregation. Neuroinflammation is a hallmark of tauopathies and evidence is growing for a role of CD8+ T cells in disease pathogenesis. CD8+ T cells release granzyme proteases but what role these proteases play in neuronal dysfunction is currently lacking. Here, we identified that granzyme A (GzmA) is present in brain tissue and proteolytically cleaves tau. Mass spectrometric analysis of tau fragments produced on digestion of tau with GzmA identified three cleavage sites at R194-S195, R209-S210 and K240-S241. Mutation of the critical Arg or Lys residues at the cleavage sites in tau or chemical inhibition of GzmA blocked the proteolysis of tau by GzmA. Development of a semi-targeted mass spectrometry approach identified peptides in tauopathy brain tissue corresponding to proteolysis by GzmA at R209-S210 and K240-S241 in tau. When expressed in cells the GzmA-cleaved C-terminal fragments of tau were highly phosphorylated and aggregated upon incubation of the cells with tauopathy brain seed. The C-terminal fragment tau195–441 was able to transfer between cells and promote aggregation of tau in acceptor cells, indicating the propensity for such tau fragments to propagate between cells. Collectively, these results raise the possibility that GzmA, released from infiltrating cytotoxic CD8+ T cells, proteolytically cleaves tau into fragments that may contribute to its pathological properties in tauopathies. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignant tumor that threatens women's life and health, and metastasis often occurs in the advanced stage of breast cancer, leading to pathological bone destruction and seriously reducing patient quality of life. In this study, we coupled chlorin e6 (Ce6) with mono-(6-amino-6-deoxy)-beta-cyclodextrin (β-CD) to form Ce6-CD, and combined ferrocene with the FFVLG3C peptide and PEG chains to form the triblock molecule Fc-pep-PEG. In addition, the IDO-1 inhibitor NLG919 was loaded with Ce6-CD and Fc-pep-PEG to construct the supramolecular nanoparticle NLG919@Ce6-CD/Fc-pep-PEG (NLG919@CF). After laser irradiation, Ce6 produced robust reactive oxidative species to induce tumor cell apoptosis. Simultaneously, ferrocene became charged, and Fc-pep-PEG dissociated from the spherical nanoparticles, enabling their transformation into nanofibers, which increased both the retention effect and the induction of ferroptosis. The released NLG919 reduced the number of regulatory T cells (Tregs) and restored the function of cytotoxic T lymphocytes (CTLs) by inhibiting the activity of IDO-1. Moreover, combined administration with an anti-PD-1 antibody further relieved immune suppression in the tumor microenvironment. This article presents a new strategy for the clinical treatment of breast cancer with bone metastasis and osteolysis. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells are a subset of lipid-reactive, unconventional T cells that have anti-tumor properties that make them a promising target for cancer immunotherapy. Recent studies have deciphered the developmental pathway of human MAIT and Vγ9Vδ2 γδ-T cells as well as murine iNKT cells, yet our understanding of human NKT cell development is limited. Here, we provide an update in our understanding of how NKT cells develop in the human body and how knowledge regarding their development could enhance human treatments by targeting these cells. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing. Regulatory T cells (Tregs) are known for suppressing inflammatory processes, but their full capacity for tissue regeneration is yet to be harnessed. Here, the authors demonstrate the efficiency of Tregs in facilitating tissue healing in mouse models of bone, muscle, and skin injury, with monocytes/macrophages and interleukin-10 playing a key mechanistic role in the process. [ABSTRACT FROM AUTHOR]

With the revolutionary progress of immune checkpoint inhibitors (ICIs) in non–small cell lung cancer, identifying patients with cancer who would benefit from ICIs has become critical and urgent. Here, we report protein tyrosine phosphatase receptor type T (PTPRT) loss as a precise and convenient predictive marker independent of PD-L1 expression for anti–PD-1/PD-L1 axis therapy. Anti–PD-1/PD-L1 axis treatment markedly increased progression-free survival in patients with PTPRT-deficient tumors. PTPRT-deficient tumors displayed cumulative DNA damage, increased cytosolic DNA release, and higher tumor mutation burden. Moreover, the tyrosine residue 240 of STING was identified as a direct substrate of PTPRT. PTPRT loss elevated phosphorylation of STING at Y240 and thus inhibited its proteasome-mediated degradation. PTPRT-deficient tumors released more IFN-β, CCL5, and CXCL10 by activation of STING pathway and increased immune cell infiltration, especially of CD8 T cells and natural killer cells, ultimately enhancing the efficacy of anti–PD-1 therapy in multiple subcutaneous and orthotopic tumor mouse models. The response of PTPRT-deficient tumors to anti–PD-1 therapy depends on the tumor-intrinsic STING pathway. In summary, our findings reveal the mechanism of how PTPRT-deficient tumors become sensitive to anti–PD-1 therapy and highlight the biological function of PTPRT in innate immunity. Considering the prevalence of PTPRT mutations and negative expression, this study has great value for patient stratification and clinical decision-making. Editor's summary: Non–small cell lung cancer can be treated with anti–programmed death 1/ligand 1 (anti–PD-1/L1); however, biomarkers for response are imprecise. Here, Chen et al. evaluate the loss of protein tyrosine phosphatase receptor type T (PTPRT) as a predictor of response to anti–PD-1/L1 therapy. They show in mouse models that PTPRT-deficient tumors rely on the STING pathway to respond to anti–PD-1 therapy, and this study can help stratify patients who would benefit from this therapy. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

The early diagnosis of liver cancer is crucial for the treatment and depends on the coordinated use of several test procedures. Early diagnosis is crucial for precision therapy in the treatment of the hepatocellular carcinoma (HCC). Therefore, in this study, the NK cell-related gene prediction model was used to provide the basis for precision therapy at the gene level and a novel basis for the treatment of patients with liver cancer. Natural killer (NK) cells have innate abilities to recognize and destroy tumor cells and thus play a crucial function as the "innate counterpart" of cytotoxic T cells. The natural killer (NK) cells is well recognized as a prospective approach for tumor immunotherapy in treating patients with HCC. In this research, we used publicly available databases to collect bioinformatics data of scRNA-seq and RNA-seq from HCC patients. To determine the NK cell-related genes (NKRGs)-based risk profile for HCC, we isolated T and natural killer (NK) cells and subjected them to analysis. Uniform Manifold Approximation and Projection plots were created to show the degree of expression of each marker gene and the distribution of distinct clusters. The connection between the immunotherapy response and the NKRGs-based signature was further analyzed, and the NKRGs-based signature was established. Eventually, a nomogram was developed using the model and clinical features to precisely predict the likelihood of survival. The prognosis of HCC can be accurately predicted using the NKRGs-based prognostic signature, and thorough characterization of the NKRGs signature of HCC may help to interpret the response of HCC to immunotherapy and propose a novel tumor treatment perspective. [ABSTRACT FROM AUTHOR]

Adamantinomatous craniopharyngioma (ACP) is a clinically aggressive tumor without effective treatment method. Previous studies proposed a paracrine tumorigenesis model, in which oncogenic β-catenin induces senescence in pituitary stem cells and the senescent cells lead the formation of paracrine tumors through secretion of pro-tumorigenic factors. However, there lacks characterization on senescent cells in ACPs. Here, we profiled 12 ACPs with single-cell RNA and TCR-sequencing to elucidate the cellular atlas in ACPs and 3 of them were also subject to spatial sequencing to localize different subpopulations of the tumor cells. In total, we obtained the transcriptome profiles of 70,682 cells. Tumor cells, which were unambiguously identified through the cellular mutation status of the driver CTNNB1 mutations, were clustered into 6 subsets. The whorl-like cluster (WC) cells show distinct molecular features from the other tumor cells and the palisading epithelium (PE) cells consists of a proliferating subset. Other than typical PE and WC, we identified two novel subpopulations of the tumor cells. In one subpopulation, the cells express a high level of cytokines, e.g., FDCSP and S100A8/A9, and are enriched with the senescence-associated secretory phenotype (SASP) factors. Hematoxylin and eosin staining reveals that these SASP cells lack an ordered structures and their nuclei are elongated. In the other subpopulation, the cell sizes are small and they are tightly packed together with an unusual high density expressing a high level of mitochondrial genes (median 10.9%). These cells are the origin of the tumor developmental trajectories revealed by RNA velocity and pseudo-time analysis. Single-cell RNA and TCR analysis reveals that some ACPs are infiltrated with clonally expanded cytotoxic T cells. We propose a hypothesis that WC and PE are formed via different negative regulation mechanisms of the overactivated WNT/β-catenin signaling which provides a new understanding on the tumorigenesis of ACPs. The study lays a foundation for future studies on targeting senescent cells in ACPs with senolytic compounds or other therapeutic agents. [ABSTRACT FROM AUTHOR]

Due to the genetic diversity between the mother and the fetus, heightened control over the immune system during pregnancy is crucial. Immunological parameters determined by clinicians in women with idiopathic recurrent spontaneous abortion (RSA) include the quantity and activity of Natural Killer (NK) and Natural Killer T (NKT) cells, the quantity of regulatory T lymphocytes, and the ratio of pro-inflammatory cytokines, which indicate imbalances in Th1 and Th2 cell response. The processes are controlled by immune checkpoint proteins (ICPs) expressed on the surface of immune cells. We aim to investigate differences in the expression of ICPs on T cells, T regulatory lymphocytes, NK cells, and NKT cells in peripheral blood samples collected from RSA women, pregnant women, and healthy multiparous women. We aim to discover new insights into the role of ICPs involved in recurrent pregnancy loss. Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation from blood samples obtained from 10 multiparous women, 20 pregnant women (11–14th week of pregnancy), and 20 RSA women, at maximum of 72 h after miscarriage. The PBMCs were stained for flow cytometry analysis. Standard flow cytometry immunophenotyping of PBMCs was performed using antibodies against classical lymphocyte markers, including CD3, CD4, CD8, CD56, CD25, and CD127. Additionally, ICPs were investigated using antibodies against Programmed Death Protein-1 (PD-1, CD279), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3, CD366), V-domain Ig suppressor of T cell activation (VISTA), T cell immunoglobulin and ITIM domain (TIGIT), and Lymphocyte activation gene 3 (LAG-3). We observed differences in the surface expression of ICPs in the analyzed subpopulations of lymphocytes between early pregnancy and RSA, after miscarriage, and in women. We noted diminished expression of PD-1 on T lymphocytes (p = 0.0046), T helper cells (CD3CD4 positive cells, p = 0.0165), T cytotoxic cells (CD3CD8 positive cells, p = 0.0046), T regulatory lymphocytes (CD3CD4CD25CD127 low positive cells, p = 0.0106), and NKT cells (CD3CD56/CD16 positive cells, p = 0.0438), as well as LAG-3 on lymphocytes T (p = 0.0225) T helper, p = 0.0426), T cytotoxic cells (p = 0.0458) and Treg (p = 0.0293), and cells from RSA women. Impaired expression of TIM-3 (p = 0.0226) and VISTA (p = 0.0039) on CD8 cytotoxic T and NK (TIM3 p = 0.0482; VISTA p = 0.0118) cells was shown, with an accompanying increased expression of TIGIT (p = 0.0211) on NKT cells. The changes in the expression of surface immune checkpoints indicate their involvement in the regulation of pregnancy. The data might be utilized to develop specific therapies for RSA women based on the modulation of ICP expression. [ABSTRACT FROM AUTHOR]

Background/Objectives: Oral Lichen Planus (OLP) is a common immune-mediated inflammatory disorder affecting the oral mucosa, impacting 0.5% to 2% of the global population, primarily middle-aged women. Immunological dysregulation is a key factor in OLP's pathogenesis, involving CD4+ T helper and CD8+ T cytotoxic cells. The World Health Organization (WHO) classifies OLP as a potentially malignant disorder, with a risk of oral squamous cell carcinoma (OSCC) developing in up to 2% of lesions. This narrative review aims to provide a comprehensive overview of the etiopathogenesis, clinical manifestations, diagnostic criteria, and therapeutic strategies for OLP, informing clinical practice and guiding future research. Methods: A review of the literature from the PubMed and Google Scholar databases was conducted up to December 2023, focusing on studies addressing the etiopathogenesis, diagnosis, clinical manifestations, and treatment of OLP. Results: OLP's pathogenesis is driven by immune dysregulation, with CD4+ and CD8+ cells playing crucial roles. Clinically, OLP presents as reticular, erosive, bullous, and plaque-like lesions. Diagnosis relies on clinical examination, histopathology, and direct immunofluorescence. Recent advancements in diagnostic markers and imaging techniques have improved detection and monitoring. Treatment primarily involves corticosteroids, but novel therapies such as curcumin, retinoids, and laser therapy are increasingly used for their effectiveness and reduced side effects. These treatments show promise in symptom reduction and recurrence prevention, although long-term data are needed. Conclusions: Regular screenings and biopsies are essential due to OLP's likelihood of malignant transformation. This study urges further investigation into long-term results, improved diagnostic techniques, and evidence-based treatment regimens. [ABSTRACT FROM AUTHOR]

Background: In advanced head and neck cancer (HNC) patients, 50–60% experience loco-regional relapse and distant metastasis. Boron neutron capture therapy (BNCT) has shown remarkable therapeutic response in recurrent HNC, but there is still a 70% chance of local recurrence. This study aimed to identify a suitable liquid biomarker to assess patient response following BNCT. Myeloid-derived suppressor cells (MDSCs) are immune-suppressive cells that inhibit cytotoxic T cells. Circulating MDSC levels have been linked to the clinical stage and prognosis in HNSCC. Methods: Five patients with recurrent head and neck cancer underwent a treatment regimen that commenced with BNCT, followed by fractionated image-guided intensity-modulated radiotherapy (IG-IMRT). Liquid biopsy analysis via flow cytometry and tumor volume analysis by clinical imaging were conducted at three stages: before BNCT, before the first fraction of IG-IMRT, and one month after the last fraction of IG-IMRT. Results: Compared to other MDSC subtypes, monocytic MDSCs (M-MDSCs) exhibited a notable correlation with tumor volume. This strong correlation was observed at all testing time points except one month after BNCT treatment. Conclusions: This case series highlights a strong link between tumor size and circulating M-MDSC levels before BNCT and one month after the last IG-IMRT treatment in recurrent head and neck cancer patients. These results suggest that the level of circulating M-MDSCs could be a marker for monitoring tumor progression in recurrent HNC patients following radiation therapy, including BNCT. [ABSTRACT FROM AUTHOR]

Objective(s): In this study, the adjuvant activity of aqueous and alcoholic extracts of propolis was examined on the inactivated herpes simplex virus-1 (HSV-1). Materials and Methods: BALB/C mice were administered with inactivated (HSV-1; the KOS strain) plus alcoholic and aqueous extracts, followed by assessment of the cellular and humoral immune responses. Results: Alcoholic and aqueous extracts, as an adjuvant, revealed a significant increase in lymphocyte proliferation and cytotoxic T lymphocyte (CTL) responses versus the HSV-1 group. In addition, HSV-1 plus alcoholic extract showed a remarkable increase in IFN-γ cytokine and IFN-γ/IL-4 ratio. On the other hand, both alcoholic and aqueous extracts in the HSV-1 vaccine suppressed the IL-4 cytokine response as compared with the HSV-1 vaccine. In addition, HSV-1 plus alcoholic extract showed a significant increment in IgG1, IgG2a, and IgG2b isotypes as compared with the HSV-1 vaccine. Conclusion: Propolis extracts seem to modulate the immune response against inactivated HSV-1 model and can be used as a suitable vaccine adjuvant or a component of a complex adjuvant against infectious diseases. [ABSTRACT FROM AUTHOR]

Human Leukocyte Antigen (HLA) is like a device that monitors the internal environment of the body. T lymphocytes immediately recognize the HLA molecules that are expressed on the surface of the cells of the different individual, attacking it defeats microorganisms that is one of the causes of rejection in organ transplants performed between people with unmatched HLA types. Over 2850 and 3580 different polymorphisms have been reported for HLA-A and HLA-B respectively, around the world. HLA genes are associated with the risk of developing a variety of diseases, including autoimmune diseases, and play an important role in pathological conditions. By using a deep learning method called multi-task learning to simultaneously predict the gene sequences of multiple HLA genes, it is possible to improve accuracy and shorten execution time. Some new systems use a model called convolutional neural network (CNNs) in deep learning, which uses neural networks consisting of many layers and can learn complex correlations between SNP information and HLA gene sequences based on reference data for HLA imputation, which serves as training data. The learned model can output predicted values of HLA gene sequences with high accuracy using SNP information as input. To investigate which part of the input information surrounding the HLA gene is used to make learning predictions, predictions were made using not only a small number of nearby SNP information but also many SNP information distributed over a wider area by visualizing the learning information of the model. While conventional methods are strong at learning using nearly SNP information and not good at learning using SNP information located at distant locations, some new systems are thought that prediction accuracy may have improved because this problem was overcome. HLA genes are involved in the onset of a variety of diseases and are attracting attention. As an important area from the perspective of elucidating pathological conditions and realizing personalized medicine. The applied multi-task learning to two different HLA imputation reference panels—a Japanese panel (n = 1118) and type I diabetes genetics consortium panel (n = 5122). Through 10-fold cross-validation on these panels, the multi-task learning achieved higher imputation accuracy than conventional methods, especially for imputing low-frequency and rare HLA alleles. The increased prediction accuracy of HLA gene sequences is expected to increase the reliability of HLA analysis, including integrated analysis between different racial populations, and is expected to greatly contribute to the identification of HLA gene sequences associated with diseases and further elucidation of pathological conditions. [ABSTRACT FROM AUTHOR]

In this paper, we develop a diffusive and delayed hepatitis B virus (HBV) infection model, which incorporates both virus‐to‐cell and cell‐to‐cell transmissions along with cytotoxic T lymphocyte (CTL) immune response. Two threshold parameters ℜ0$$ {\mathfrak{\Re}}_0 $$ (basic reproduction number) and ℜ1$$ {\mathfrak{\Re}}_1 $$ (immune response reproduction number) are defined, which determine the dynamic behavior of the model. Employing the approach of Lyapunov functionals, we show that the infection‐free steady state is globally asymptotically stable when ℜ0≤1$$ {\mathfrak{\Re}}_0\le 1 $$; the immune‐free infected steady state is globally asymptotically stable when ℜ1≤1<ℜ0$$ {\mathfrak{\Re}}_1\le 1<{\mathfrak{\Re}}_0 $$; and the immune‐present steady state is globally asymptotically stable when ℜ0>1,ℜ1>1$$ {\mathfrak{\Re}}_0>1,{\mathfrak{\Re}}_1>1 $$, and φ(I)=I$$ \varphi (I)=I $$. We perform the sensitivity and uncertainly analysis on ℜ0$$ {\mathfrak{\Re}}_0 $$ with respect to parameters and find that the most important parameter that drives the HBV infection is the mortality of HBV DNA capsids. Moreover, the theoretical results are supported with numerical simulations. [ABSTRACT FROM AUTHOR]

The naked mole rat (Heterocephalus glaber, NMR) is a rodent with exceptional longevity, low rates of age‐related diseases and spontaneous carcinogenesis. The NMR represents an attractive animal model in longevity and cancer research, but there are no NMR‐specific antibodies available to study its immune system with respect to age‐ and cancer‐related questions. Substantial homology of major NMR immune cell markers with those of Guinea pig, human and, to a lesser extent, mouse and rat origin are implicated for the existence of immunological cross‐reactivity. We identified 10 antibodies recognising eight immunophenotypic markers expressed on the NMR's T and B lymphocytes, macrophages/monocytes and putative haematopoietic precursors and used them for an immunophenotyping of leukocyte subsets of peripheral blood, spleen and bone marrow samples. Overall, we found that the leukocyte composition of NMR peripheral blood is comparable to that of mice. Notably, the frequency of cytotoxic T cells was found to be lower in the NMR compared to corresponding mouse tissues and human blood. Antibodies used in the present paper are available either commercially or from the scientific community and will provide new opportunities for the NMR as a model system in ageing‐ and cancer‐related research areas. [ABSTRACT FROM AUTHOR]

Abstract This paper is mainly concerned with an investigation of antigen-driven T-cell infection process through a mathematical model. Several mathematical models have been introduced in the literature in order to gain insights into the dynamics of the disease progression, however, the results considering the effect of multiple factors which include antigen-driven CD4 T-cell progress, latent infection stage, activation of CTLs response, role of antiretroviral therapies (ARTs) and possibilities of multiple time-delays during the infection process are not involved. Hence, the paper introduces a six-dimensional virus infection model by involving the above factors. Particularly, (i) the effect of activation of antigen-specific T-cells; (ii) the effect of the maturation of infected cells; (iii) effect of multiple time delays, that is, during the interaction between susceptible and infectious and during the activation of immune responses; which play a significant role in preventing and modulating the Human Immunodeficiency Virus (HIV). The main aim of the paper to analyze the local and global stability of the class of mathematical models regarding the effect of time delays which provides a better pathway to the infection progress. Finally, the overall contribution of the present work is listed as follows: (1) by constructing the suitable Lyapunov functional, the global stability of the intracellular delayed model is derived; (2) detailed Hopf-bifurcation analysis is discussed with respect to immune response delay. The numerical simulation is performed to validate the effectiveness and applicability of the theoretical predictions. [ABSTRACT FROM AUTHOR]

In this paper, we incorporate immune systems into an HIV model, which considers both logistic target-cell proliferation and viral cell-to-cell transmission. We study the dynamics of this model including the existence and stability of equilibria. Based on the existence of equilibria, we focus on the backward bifurcation and forward bifurcation. Considering the stability of equilibria, Hopf bifurcation is discussed by identifying the basic reproduction number R 0 as bifurcation parameter. The direction and stability of Hopf bifurcation are investigated by computing the first Lyapunov exponent. Specially, the effects of immune response on the basic reproduction number R 0 and viral dynamics are addressed by deriving the sensitivity analysis. As a result, we find that the removal rate of infected cells by cytotoxic T lymphocytes (CTLs), γ 1 , is the predominant factor of R 0 . However, we conclude from numerical results that it is unfeasible to decrease R 0 by increasing the value of γ 1 constantly. Numerical simulation is also presented to demonstrate the applicability of the theoretical predictions. These dynamics are investigated by the proposed model to point out the importance and complexity of immune responses in fighting HIV replication. [ABSTRACT FROM AUTHOR]

The dynamics of a model describing the human immunodeficiency virus (HIV) infection with cytotoxic T-lymphocyte (CTL), antibodies and two saturated rates is investigated and studied in this paper. The model includes five nonlinear differential equations describing the evolution of uninfected cells, infected ones, free HIV viruses, CTL immune response and antibodies. This model includes also two treatments that represent the efficiency of drug treatment in inhibiting viral production and preventing new infections. Existence, positivity and boundedness of solutions are given. Existence of the optimal control pair is established and the Pontryagin's maximum principle is used to find an optimal treatment strategy that maximizes the number of uninfected CD4+ T cells as well as cytotoxic T-lymphocyte and antibody immune responses. Finally, the optimality system is derived and solved numerically. Results show that administrating good therapy maximizes the amount of healthy CD4+ T cells and deceases considerably the viral load and the infected cells. [ABSTRACT FROM AUTHOR]

This paper investigates the stochastic HTLV-I infection model with CTL immune response, and the corresponding deterministic model has two basic reproduction numbers. We consider the nonlinear CTL immune response for the interaction between the virus and the CTL immune cells. Firstly, for the theoretical needs of system dynamical behavior, we prove that the stochastic model solution is positive and global. In addition, we obtain the existence of ergodic stationary distribution by stochastic Lyapunov functions. Meanwhile, sufficient condition for the extinction of the stochastic system is acquired. Reasonably, the dynamical behavior of deterministic model is included in our result of stochastic model when the white noise disappears. [ABSTRACT FROM AUTHOR]

Many mRNA-based vaccines have been investigated for their specific potential to activate dendritic cells (DCs), the highly-specialized antigen-presenting cells of the immune system that play a key role in inducing effective CD4+ and CD8+ T-cell responses. In this paper we report a new vaccine/gene delivery platform that demonstrates the benefits of using a self-amplifying (“replicon”) mRNA that is protected in a viral-protein capsid. Purified capsid protein from the plant virus Cowpea Chlorotic Mottle Virus (CCMV) is used to in vitro assemble monodisperse virus-like particles (VLPs) containing reporter proteins (e.g., Luciferase or eYFP) or the tandem-repeat model antigen SIINFEKL in RNA gene form, coupled to the RNA-dependent RNA polymerase from the Nodamura insect virus. Incubation of immature DCs with these VLPs results in increased activation of maturation markers – CD80, CD86 and MHC-II – and enhanced RNA replication levels, relative to incubation with unpackaged replicon mRNA. Higher RNA uptake/replication and enhanced DC activation were detected in a dose-dependent manner when the CCMV-VLPs were pre-incubated with anti-CCMV antibodies. In all experiments the expression of maturation markers correlates with the RNA levels of the DCs. Overall, these studies demonstrate that: VLP protection enhances mRNA uptake by DCs; coupling replicons to the gene of interest increases RNA and protein levels in the cell; and the presence of anti-VLP antibodies enhances mRNA levels and activation of DCs in vitro. Finally, preliminary in vivo experiments involving mouse vaccinations with SIINFEKL-replicon VLPs indicate a small but significant increase in antigen-specific T cells that are doubly positive for IFN and TFN induction. [ABSTRACT FROM AUTHOR]

In this paper, we construct an infection-age model to study the interaction between viruses and the immune system within the host. In the model, the mortality rate of infected cells, the rate that cytotoxic T lymphocytes (CTL) kill infected cells, the rate that infected cells produce new virus, and the CTL proliferate rate may depend on the infection-age. The basic reproduction number and the threshold for the existence of steady states are obtained. Local stability of both the infection-free and infection steady states is studied by analyzing the linearized systems. Global stability of the infection-free steady state is obtained by investigating a renewal integral equation and global stability of the infection steady state is obtained by constructing a Liapunov functional. Numerical simulations are presented to verify the theoretical results. [ABSTRACT FROM AUTHOR]

Antimicrobial peptides are essential components of innate defense mechanisms and make promising candidates for novel anti-infective agents. The advantages of these peptides in clinical applications include their potential for broad-spectrum and rapid bactericidal activities, and low propensity for resistance development, whereas possible disadvantages include their high cost, limited stability, and unknown toxicology and pharmacokinetics. Granulysin (Gr) is a cytolytic and proinflammatory molecule expressed by activated human cytotoxic T lymphocytes and natural killer (NK) cells. This paper aims to study bacteriostatic and bactericidal activity against Mycobacterium tuberculosis by synthetic analogues of human Gr between 12 and 26 amino acids (AA) and their acyl derivatives. Considering results of previous studies, five new peptides were designed: a cyclic of 20 AA (Gr-SL1); one of 21 AA (linear) (Gr-SL2), another of 12 AA (cyclic) (Gr-SL3) and two lipopeptides (Gr-SL3-lauric and Gr-SL3-palmitic). Peptides were manually synthesized as C-terminal carboxamides by the solid-phase method following Fmoc chemistry. Gr synthetic analogues were purified by reverse phase HPLC and analyzed by analytical C18RP-HPLC and Maldi Tof. The antimycobacterial activity of synthesized Gr analogues was assessed using a microdilution susceptibility test as described previously. Although peptides studied here had neither higher antimycobacterial activity nor lower toxicity than analogs of human Gr previously evaluated, fresh knowledge concerning the influence of acylation and structural aspects analyzed will optimize the design of novel peptides combining the most favorable aspects for the maintenance of antimycobacterial activity with minimum toxicity. [ABSTRACT FROM AUTHOR]

The goal of this paper is to investigate the dynamical behavior of a general nonlinear delayed viral infection model with cytotoxic T lymphocyte (CTL) immune response. The intrinsic growth rate of uninfected hepatocytes, incidence rate of infection, removal rate of infected hepatocytes and capsids, production and removal rate of viruses, activation rate of CTLs, and decay rate of CTLs are given by general nonlinear functions with a set of conditions on these general nonlinear functions, which make the analysis of the model more difficult. The global threshold dynamics with respect to the reproduction numbers for viral infection R0 and for CTL immune response R1 have been presented by constructing suitable Lyapunov functionals. Numerical simulations are carried out for a model with specific forms of the general functions to confirm the theoretical results and show that both the numerical and theoretical results are consistent. [ABSTRACT FROM AUTHOR]

This paper studies a mathematical model for the interaction between tumor cells and Cytotoxic T lymphocytes (CTLs) under drug therapy. We obtain some sufficient conditions for the local and global asymptotical stabilities of the system by using Schur–Cohn criterion and the theory of Lyapunov function. In addition, it is known that the system without any treatment may undergo Neimark–Sacker bifurcation, and there may exist a chaotic region of values of tumor growth rate where the system exhibits chaotic behavior. So it is important to narrow the chaotic region. This may be done by increasing the intensity of the treatment to some extent. Moreover, for a fixed value of tumor growth rate in the chaotic region, a threshold value γ 0 is predicted of the treatment parameter γ. We can see Neimark–Sacker bifurcation of the system when γ = γ 0 , and the chaotic behavior for tumor cells ends and the system becomes locally asymptotically stable when γ > γ 0 . [ABSTRACT FROM AUTHOR]

Nasal-type extranodal natural killer/T-cell lymphoma (ENKTL-NT) is a special subtype of non-Hodgkin' s lymphoma derived from natural killer cells or cytotoxic T cells. Oral ulcers as the first symptom makes its diagnosis challenging because of its rarity and lack of understanding. We report a case of ENKTL-NT in this paper. We analyzed the clinicopathological features, differential diagnosis, treatment, prognosis and the causes of misdiagnosis to provide a diagnostic basis for dentists to make better clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

In this Q&A, Cell Press Community Review Scientific Editor Leia Judge talks to Dr. Clint Allen and Dr. Sandro Santagata about their new papers "Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer" and "Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma" and their experiences with publishing through Cell Press Community Review. [ABSTRACT FROM AUTHOR]

Abstract: Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell lines). A growing understanding of the PKs, dosing, and timing of administration of alemtuzumab has allowed for the study of its use as a conditioning agent for allogeneic HCT. The highly immunosuppressive properties of the drug are particularly appealing in the setting of non‐malignant HCT, where GVHD provides no clinical benefit and relapse of malignancy is not applicable. In addition, the degree of immune suppression achieved with alemtuzumab has allowed for a reduction in the intensity of myeloablative cytotoxic agents included in some HCT conditioning regimens, allowing for fewer acute and late toxicities. This review paper will provide a comprehensive summary of the mechanism of action, PKs, dosing, and timing of alemtuzumab, a brief description of its use in various allogeneic HCT protocols for non‐malignant conditions and a summary of the data regarding its use for GVHD therapy. The goal of this review was to provide an understanding as to how alemtuzumab might be safely incorporated into HCT conditioning regimens for children with non‐malignant disease, allowing for expanded access to curative HCT therapy. [ABSTRACT FROM AUTHOR]

Oncolytic virus (OV) is a replication competent virus that selectively invades cancer cells; as these cells die under the viral burden, the released virus particles proceed to infect other cancer cells. Oncolytic viruses are designed to also be able to stimulate the anticancer immune response. Thus, one may represent an OV by two parameters: its replication potential and its immunogenicity. In this paper we consider a combination therapy with OV and a checkpoint inhibitor, anti-PD-1. We evaluate the efficacy of the combination therapy in terms of the tumor volume at some later time, for example, 6 months from initial treatment. Since T cells kill not only virus-free cancer cells but also virus-infected cancer cells, the following question arises: Does increasing the amount of the checkpoint inhibitor always improve the efficacy? We address this question, by a mathematical model consisting of a system of partial differential equations. We use the model to construct, by simulations, an efficacy map in terms of the doses of the checkpoint inhibitor and the OV injection. We show that there are regions in the map where an increase in the checkpoint inhibitor actually decreases the efficacy of the treatment. We also construct efficacy maps with checkpoint inhibitor vs. the replication potential of the virus that show the same antagonism, namely, an increase in the checkpoint inhibitor may actually decrease the efficacy. These results have implications for clinical trials. [ABSTRACT FROM AUTHOR]

The aim of this paper is to study the early stage of HBV infection and impact delay in the infection process on the adaptive immune response, which includes cytotoxic T-lymphocytes and antibodies. In this stage, the growth of the healthy hepatocyte cells is logistic while the growth of the infected ones is linear. To investigate the role of the treatment at this stage, we also consider two types of treatment: interferon-α (IFN) and nucleoside analogues (NAs). To find the best strategy to use this treatment, an optimal control approach is developed to find the possibility of having a functional cure to HBV. [ABSTRACT FROM AUTHOR]

Cross-presentation of apoptotic cell associated antigens by immature dendritic cells prevents the activation of self reactive CD8 T cells. Tolerized self reactive CD8 T cells down-regulate IL-7R expression on their surface. Whether over-expression of IL-7R can reverse their fate and function has not been examined. In this paper, we showed forced expression of IL-7R in OT-I T cells by a transgene enhanced CD8 T cell mediated diabetes in the RIP-mOVA model. Although IL-7R Tg (transgenic) did not completely reverse the deletion of OT-I T cells, it provided a significant survival advantage over w.t OT-I T cells. Furthermore, IL7R Tg OT-I T cells isolated from diabetic pancreata displayed increased production of IFN-γ, higher expression of T-bet, and increased externalization of CD107a. We also found that immature DCs containing apoptotic cells expressed high levels of PDL-1 on their surface. Although IL-7R Tg did not change PD1 expression on activated OT-I cells in vivo, the transgene enabled a significantly lower number of OT-I T cells to induce diabetes in the absence of PDL-1. Our results demonstrated that forced expression of IL-7R not only improved the functionality of tolerized CD8 T cells, it also acted in synergy with PDL-1 deficiency to further promote CD8 T cell cytotoxicity to self antigens. [ABSTRACT FROM AUTHOR]

In this paper, a pathogen dynamics model with capsids and saturated incidence has been proposed and analyzed. Cytotoxic T Lymphocyte (CTL) immune response and two distributed time delays have been incorporated into the model. The nonnegativity and boundedness of the solutions of the proposed model have been shown. Two threshold parameters which fully determine the existence and stability of the three steady states of the model have been computed. Using the method of Lyapunov function, the global stability of the steady states of the model has been established. The theoretical results have been confirmed by numerical simulations. [ABSTRACT FROM AUTHOR]