Search

ObjectivesEvidence suggests that B cell-depleting therapy with rituximab (RTX) affects humoral immune response after vaccination. It remains unclear whether RTX-treated patients can develop a humoral and T-cell-mediated immune response against SARS-CoV-2 after immunisation.MethodsPatients under RTX treatment (n=74) were vaccinated twice with either mRNA-1273 or BNT162b2. Antibodies were quantified using the Elecsys Anti-SARS-CoV-2 S immunoassay against the receptor-binding domain (RBD) of the spike protein and neutralisation tests. SARS-CoV-2-specific T-cell responses were quantified by IFN-γ enzyme-linked immunosorbent spot assays. Prepandemic healthy individuals (n=5), as well as healthy individuals (n=10) vaccinated with BNT162b2, served as controls.ResultsAll healthy controls developed antibodies against the SARS-CoV-2 RBD of the spike protein, but only 39% of the patients under RTX treatment seroconverted. Antibodies against SARS-CoV-2 RBD significantly correlated with neutralising antibodies (τ=0.74, p+ peripheral B cells (n=36) did not develop specific antibodies, except for one patient. Circulating B cells correlated with the levels of antibodies (τ=0.4, pConclusionsThe data suggest that vaccination can induce SARS-CoV-2-specific antibodies in RTX-treated patients, once peripheral B cells at least partially repopulate. Moreover, SARS-CoV-2-specific T cells that evolved in more than half of the vaccinated patients may exert protective effects independent of humoral immune responses.

Objective. To analyze T cell-mediated immunity (subpopulations of CD3+, CD4+, and CD8+ lymphocytes) in HIV-infected patients with helminthiasis receiving or not receiving antiretroviral therapy (ART). Patients and methods. This study included 159 individuals; 100 of them had subclinical stage 3 HIV infection and helminthiasis (caused by different helminths) and were divided into two experimental groups depending on whether they received ART or not. The control group 1 comprised 29 HIV-positive people without helminthiasis not receiving ART, whereas the control group 2 included 30 HIV-negative people with helminthiasis. Patients in the experimental groups and control group 2 were followed up during the study and received anthelmintic treatment. The assessment of the immune status using monoclonal antibodies against specific antigens of subpopulations of T-lymphocytes (CD3+, CD4+ cells, cytotoxic T-cells-suppressors-CD8+ and CD4+/CD8+ ratio) was performed in the laboratory of the Republican Center for the Prevention and Control of AIDS and Infectious Diseases, Ufa, Russian Federation. Results. In this study, we evaluated the relative count of CD3+, CD4+, and CD8+ T cells in HIV-infected patients with helminthiasis at different time-pints during 6 months. We observed significant differences in the CD3+, CD3+CD4+, and CD3+CD8+ cell count between HIV-infected patients with helminthiasis on ART and without ART. Patients in the experimental group on ART demonstrated a significantly lower CD3+ cell count compared to patients in the experimental group not on ART (2.3 times lower; p < 0.01), as well as lower CD3+CD4+ cell count (1.5 times lower; p < 0.05) and CD4+CD8+ cell count (1.9 times lower; p < 0.05). Our findings suggest that HIV-infected people with helminthiasis on ART are more likely to have their CD3+, CD4+, and CD8+ Т-cell count normalized than those not receiving ART. Conclusion. The assessment of the immune status (T-cell medicated immunity) in the study groups demonstrated that HIVinfected patients with helminthiasis on ART presented with a gradual increase of the relative CD3+ cell count throughout the study (62.5 ± 5.6 %), whereas HIV-infected patients with helminthiasis receiving no ART presented with a gradual decrease of the relative CD3+ cell count (28.0 ± 4%). HIV-infected patients without helminthiasis and receiving no ART (control group 1) also demonstrated a decrease of the relative CD3+ cell count (28.1 ± 3.5%). We also observed a clear trend towards the normalization of relative CD3+CD4+ T-cell count (41.4 ± 8.2%) in HIV-infected patients with helminthiasis on ART, while patients from other groups (including HIV-infected patients with helminthiasis without ART and individuals in both control groups) demonstrated a tendency to a steady decline in the relative CD3+CD4+ cell count at all time-points. We also found that HIV-infected patients with helminthiasis on ART had their CD4+/CD8+ ratio back to almost normal by month 6 (45.7 ± 3.7%), whereas HIV-infected patients with helminthiasis without ART and patients from the control group 1 had their mean CD4+CD8+ ratio gradually decreasing throughout the study (27.5 ± 4.9% and 30.5 ± 7.1% respectively). The parameters of T-cell mediated immunity (subpopulations of CD3+, CD4+, and CD8+ lymphocytes) showed a more pronounced tendency to normalization in HIV-infected patients with helminthiasis who received ART. Our findings suggest that in HIV-infected patients with helminthiasis on ART, compensatory mechanisms of T-lymphocytes predominate, in contrast to HIV-infected patients with helminthiasis receiving no ART and the control group of HIV-infected patients receiving no ART, in whom we observed immunodeficiency of different grades. Key words: HIV infection, helminthiasis, T-cell immunity

The pancreatic tumour stroma is composed of phenotypically heterogenous cancer-associated fibroblasts (CAFs) with both pro- and anti-tumorigenic functions. Here, we studied the impact of calcipotriol, a vitamin D3 analogue, on the activation of human pancreatic CAFs and T cells using 2- and 3-dimensional (2D, 3D) cell culture models. We found that calcipotriol decreased CAF proliferation and migration and reduced the release of the pro-tumorigenic factors prostaglandin E2, IL-6, periostin, and leukemia inhibitory factor. However, calcipotriol promoted PD-L1 upregulation, which could influence T cell mediated tumour immune surveillance. Calcipotriol reduced T cell proliferation and production of IFN-γ, granzyme B and IL-17, but increased IL-10 secretion. These effects were even more profound in the presence of CAFs in 2D cultures and in the presence of CAFs and pancreatic tumour cell line (PANC-1) spheroids in 3D cultures. Functional assays on tumour infiltrating lymphocytes also showed a reduction in T cell activation by calcipotriol. This suggests that calcipotriol reduces the tumour supportive activity of CAFs but at the same time reduces T cell effector functions, which could compromise the patients’ tumour immune surveillance. Thus, vitamin D3 analogues appear to have dual functions in the context of pancreatic cancer, which could have important clinical implications.

Lymphocytic colitis is a subtype of microscopic colitis that is mostly seen in adults. It presents mainly as chronic nonbloody diarrhea, with the hallmark of normal or near-normal endoscopy. In this case series, we are presenting 4 pediatric patients with lymphocytic colitis with prominent apoptosis of the colonic gland epithelium. Remarkably, all the patients have genetic mutations known to be associated with autoimmune enteropathy. Three patients have a CTLA4 mutation, and 1 patient has an STAT3 mutation. These mutations were previously reported in association with inflammatory bowel disease, but a specific connection with lymphocytic colitis has not been described. This report investigates the histopathology of such lesions in children and adolescents.

Background. The timely reconstitution of the donor-derived immune system is a key factor in the prevention of such post-transplant complications as graft versus host disease, relapse or secondary tumours and various infections. These complications affect the long-term survival of patients after allogeneic stem cell transplantation.Aim — to describe the main stages of T Cell–mediated immune recovery in patients after allogeneic stem cell transplantation.General findings. T-cell–mediated immunity is responsible for anti-infective and anti-tumour immune response. The early post-transplant period is characterized by the thymus-independent pathway of T-cell recovery largely involving proliferation of mature donor T cells, which were transplanted to the patient together with hematopoietic stem cells. To a lesser extent, this recovery pathway is realized through the expansion of host naïve and memory T cells, which survived after conditioning. Thymus-dependent reconstitution involves generation of de novo naïve T cells and subsequent formation of a pool of memory T-cells providing the main immunological effects — graft versus tumour and graft versus host reactions. A better understanding of the T-cell immune reconstitution process is important for selecting optimized pre-transplant conditioning regimens and patient-specific immunosuppressive therapy approaches, thus reducing the risks of post-transplant complications and improving the long-term survival of patients after allogeneic stem cell transplantation.

Acute myeloid leukemia (AML) is a systemic, heterogeneous hematologic malignancy with poor overall survival. While some malignancies have seen improvements in clinical outcomes with immunotherapy, success of these agents in AML remains elusive. Despite limited progress, stem cell transplantation and donor lymphocyte infusions show that modulation of the immune system can improve overall survival of AML patients. Understanding the causes of immune evasion and disease progression will identify potential immune-mediated targets in AML. This review explores immunosuppressive mechanisms that alter T-cell-mediated immunity in AML.

The γδ T cell immune cell lineage has remained relatively enigmatic and under-characterised since their identification. Conversely, the insights we have, highlight their central importance in diverse immunological roles and homeostasis. Thus, γδ T cells are considered as potentially a new translational tool in the design of new therapeutics for cancer and infectious disease. Here we review our current understanding of γδ T cell biology viewed through a structural lens centred on the how the γδ T cell receptor mediates ligand recognition. We discuss the limited knowledge of antigens, the structural basis of such reactivities and discuss the emerging trends of γδ T cell reactivity and implications for γδ T cell biology.

Immunity to malaria has been linked to the availability and function of helper CD4+ T cells, cytotoxic CD8+ T cells and γδ T cells that can respond to both the asymptomatic liver stage and the symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria. John Harty and colleagues explain how different subsets of CD4+ T cells, CD8+ T cells and γδ T cells respond to the Plasmodium parasites that cause malaria. They discuss the major challenges that need to be overcome in order to harness T cell responses for malaria vaccines and therapies.

AZD1222 (ChAdOx1 nCoV-19), a replication-deficient simian adenovirus-vectored vaccine, has demonstrated safety, efficacy, and immunogenicity against coronavirus disease 2019 (COVID-19) in clinical trials and real-world studies. We characterized CD4+ and CD8+ T-cell responses induced by AZD1222 vaccination in peripheral blood mononuclear cells (PBMCs) from 280 unique vaccine recipients aged 18–85 years who enrolled in the phase 2/3 COV002 trial. Total spike-specific CD4+ T cell helper type 1 (Th1) and CD8+ T-cell responses were significantly increased in AZD1222-vaccinated adults of all ages following two doses of AZD1222. CD4+ Th2 responses following AZD1222 vaccination were not detected. Furthermore, AZD1222-specific Th1 and CD8+ T cells both displayed a high degree of polyfunctionality in all adult age groups. T-cell receptor (TCR) β sequences from vaccinated participants mapped against TCR sequences known to react to SARS-CoV-2 revealed substantial breadth and depth across the SARS-CoV-2 spike protein for the AZD1222-induced CD4+ and CD8+ T-cell responses. Overall, AZD1222 vaccination induced a robust, polyfunctional Th1-dominated T-cell response, with broad CD4+ and CD8+ T-cell coverage across the SARS-CoV-2 spike protein.One Sentence SummaryPolyfunctional CD4+ and CD8+ T-cell responses are elicited against the SARS-CoV-2 spike protein following vaccination with AZD1222

Recent evidence supports the notion that mitochondrial metabolism is necessary for T cell activation, proliferation, and function. Mitochondrial metabolism supports T cell anabolism by providing key metabolites for macromolecule synthesis and generating metabolites for T cell function. In this review, we focus on how mitochondrial metabolism controls conventional and regulatory T cell fates and function.

The immune response to viruses is a complex process involving the mobilization of a network of specialized cells and molecules that function to eliminate the infection or exert sustained control of viral replication, while avoiding damage to the host. Viral invasion leads to rapid engagement of innate immune effectors that play a crucial role in the subsequent development of adaptive immune responses, which are crucial to long-lasting protection. These phenomena are exploited in successful vaccination strategies. Our understanding of humoral and T cell-mediated immunity to viruses is also shaped by the discovery of diverse immune evasion strategies that viruses have evolved to ensure persistence in the host.

Immunomodulation and chronic inflammation are important mechanisms utilized by cancer cells to evade the immune defense and promote tumor progression. Therefore, various efforts were focused on the development of approaches to reprogram the immune response to increase the immune detection of cancer cells and enhance patient response to various types of therapy. A number of regulatory proteins were investigated and proposed as potential targets for immunomodulatory therapeutic approaches including p53 and Snail. In this study, we investigated the immunomodulatory effect of disrupting Snail-p53 binding induced by the oncogenic KRAS to suppress p53 signaling. We analyzed the transcriptomic profile mediated by Snail-p53 binding inhibitor GN25 in non-small cell lung cancer cells (A549) using Next generation whole RNA-sequencing. Notably, we observed a significant enrichment in transcripts involved in immune response pathways especially those contributing to neutrophil (IL8) and T-cell mediated immunity (BCL6, and CD81). Moreover, transcripts associated with NF-κB signaling were also enriched which may play an important role in the immunomodulatory effect of Snail-p53 binding. Further analysis revealed that the immune expression signature of GN25 overlaps with the signature of other therapeutic compounds known to exhibit immunomodulatory effects validating the immunomodulatory potential of targeting Snail-p53 binding. The effects of GN25 on the immune response pathways suggest that targeting Snail-p53 binding might be a potentially effective therapeutic strategy.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), is among the most serious infectious diseases worldwide. Adjuvanted protein subunit vaccines have been demonstrated as a kind of promising novel vaccine. This study proposed to investigate whether cytokines interliukine-7 (IL-7) and interliukine-15 (IL-15) help TB subunit vaccines induce long-term cell-mediated immune responses, which are required for vaccination against TB. In this study, mice were immunized with the M. tuberculosis protein subunit vaccines combined with adnovirus-mediated cytokines IL-7, IL-15, IL-7-IL-15, and IL-7-Linker-IL-15 at 0, 2, and 4 weeks, respectively. Twenty weeks after the last immunization, the long-term immune responses, especially the central memory-like T cells (TCM like cell)-mediated immune responses, were determined with the methods of cultured IFN-&gamma, ELISPOT, expanded secondary immune responses, cell proliferation, and protective efficacy against Mycobacterium bovis Bacilli Calmette-Guerin (BCG) challenge, etc. The results showed that the group of vaccine + rAd-IL-7-Linker-IL-15 induced a stronger long-term antigen-specific TCM like cells-mediated immune responses and had higher protective efficacy against BCG challenge than the vaccine + rAd-vector control group, the vaccine + rAd-IL-7 and the vaccine + rAd-IL-15 groups. This study indicated that rAd-IL-7-Linker-IL-15 improved the TB subunit vaccine&rsquo, s efficacy by augmenting TCM like cells and provided long-term protective efficacy against Mycobacteria.

Background VISTA (V-domain Ig suppressor of T cell activation) is a key negative immune checkpoint regulator, locking T cells in a quiescent state, unlike PD1 and CTLA4, which are expressed on activated T cells. Preclinically, VISTA monoclonal antibody treatment increased the number of tumor-specific T cells in the periphery, and enhanced the infiltration, proliferation and effector function of tumor-reactive T cells within the tumor microenvironment (TME). VISTA blockade alters the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells (DCs) within the TME leading to enhanced T cell mediated immunity. VISTA monoclonal antibody administration as a monotherapy has been shown to suppress the growth of both transplantable and inducible melanoma in preclinical models. CI-8993 is a first-in-class, fully human immunoglobulin (Ig) G1κ monoclonal antibody (mAb) against the VISTA ligand. Prior human clinical evaluation of CI-8993 demonstrated target-related clinical findings and pharmacodynamic activity at 0.15 mg/kg. Methods This phase 1 study is being conducted in the USA (NCT04475523) and is designed as a 3+3 dose escalation study beginning at 0.15 mg/kg. Patients with solid tumor malignancy (non-lymphoma) that is metastatic or unresectable and considered relapsed and/or refractory to prior therapy will be included, excluding prior CAR-T therapy or allogenic transplant. Patients will be treated with an initial step-dose of CI-8993 by IV infusion, followed by every 2 weeks of a full dose, until disease progression or toxicity. Efficacy, pharmacokinetics, pharmacodynamic and safety endpoints will be monitored and reported. Results N/A Conclusions N/A Ethics Approval The study was approved by Dartmouth-Hitchcock, Norris Cotton Cancer Center Ethics Board, approval number IRB00012031The study was approved Sarah Cannon Caner Research Institute, approval number IORG0000689

The objective of the present work was to evaluate the efficacy of a novel antigen carrier using mannosylated gelatin nanoparticles with entrapped inactivated porcine reproductive and respiratory syndrome virus (PRRSV) in inducing T cell mediated immunity in vitro. Gelatin nanoparticles (GNP) were modified with mannose to form mannosylated gelatin nanoparticles (MnGNP), which can efficiently and specifically target monocyte derived dendritic cells (MoDCs). The inactivated PRRSV was encapsulated in the MnGNP and GNP, referred to as MnGNP-PRRSV and GNP-PRRSV, respectively. All these prepared nanometer particles were characterized for size, surface charge, drug encapsulation efficiency, and drug release. The efficacy of MnGNP in targeting MoDCs was investigated, as well as the subsequent MoDCs maturation and T cell mediated cytotoxicity. The developed MnGNP-PRRSV particle was characterized with a nanometric size of 302.67 ± 3.2 nm, surface charge of 23.81 ± 1.26 mV, and PRRSV encapsulation efficiency of 63.2 ± 1.85 %. The maximum uptake of MnGNP in MoDCs in vitro was 15.5 times higher than GNP with a shorter reaction time that peaked 4 h earlier. The uptake of MnGNP-PRRSV induced maturation of MoDCs and significantly enhanced expression of SWC-3a, CD80, CD1, SLA I, SLA II on MoDCs, compared to PRRSV (p0.001). The cytokine secretion of IL-1β, IL-6, IL-10, and IL-12 was also increased in MoDCs when treated with MnGNP-PRRSV, compared to PRRSV (p0.05). The matured MoDCs triggered T lymphocytes in autologous peripheral blood mononuclear cells (PBMCs) activation, proliferation, and differentiation into effector cytotoxic T lymphocyte, suggesting increased amount of activated T cells after MnGNP-PRRSV treatment. Additionally, the function of T cells to kill PRRSV infected cells was 83.98 ± 2.62 % when triggered by MnGNP-PRRSV, compared to 60 ± 4.7 % in PRRSV group (p0.001). These results indicate that MnGNP with entrapped inactivated PRRSV can effectively and specifically target dendritic cells for maturation and activation, and subsequently improve T cell activation, proliferation and function to kill PRRSV infected cells.

Patients affected by pulmonary tuberculosis (PTB) manifest deficiencies in innate cellular immunity. The Tim3/Galectin-9 axis is an important regulator of Th1 cell immunity, leading to Th1 cell apoptosis. Herein, this study aims to clarify the underlying roles of the Tim-3/Galectin-9 axis in T-cell immunity in PTB. Peripheral blood mononuclear cells (PBMCs) were extracted from subjects with and without PTB to examine the expression of CD4, CD8, CD25, and Tim-3 under the stimulation of Mycobacterium tuberculosis (MTB) and purified protein derivative (PPD). In addition, the expression of Tim-3 and Galectin-9 in PBMCs was determined. The Tim-3/Galectin-9 axis in the PBMCs was activated or blocked to detect the secreted levels of IFN-γ, TNF-α, IL-2, and IL-22. MTB stimulation increased the expression of CD4, CD8, CD25, Tim-3, and Galectin-9 in PBMCs. The blockade of Tim-3/Galectin-9 axis resulted in reduced secretion of IFN-γ, TNF-α, IL-2, and IL-22 from T-cells. Moreover, Tim-3+CD4+T, Tim-3+CD8+, and Tim-3+CD25+T cells exhibited a greater ability to inhibit the replication of MTB in macrophages. Taken conjointly, the blockade of Tim-3/ Galectin-9 axis inhibits the secretion of inflammatory cytokines in T-cells to regulate the T-cell immunity in PTB.

The development of T cell mediated immunity relies on the assembly of a highly specialized interface between T cell and antigen presenting cell (APC), known as the immunological synapse (IS). IS assembly is triggered when the T cell receptor (TCR) binds to specific peptide antigen presented in association to the major histocompatibility complex (MHC) by the APC, and is followed by the spatiotemporal dynamic redistribution of TCR, integrins, co-stimulatory receptors and signaling molecules, allowing for the fine-tuning and integration of the signals that lead to T cell activation. The knowledge acquired to date about the mechanisms of IS assembly underscores this structure as a robust pharmacological target. The activity of molecules involved in IS assembly and function can be targeted by specific compounds to modulate the immune response in a number of disorders, including cancers and autoimmune diseases, or in transplanted patients. Here, we will review the state-of-the art of the current therapies which exploit the IS to modulate the immune response.

Ongoing research has strongly suggested the role the immune system plays in the pathogenesis of neuropathic pain. T cells appear to be one of the main regulators of the immune system with many mediators appearing to promote or suppress pain resolution. Limited effective therapies are available for treatment of neuropathic pain. Treatments available appear to modulate specific T cell with altered ratios present 3 months post treatment and parallels clinical improvement. This further supports the neuro-immune basis for neuropathic pain chronicity. Identification of novel immune mediators involved in pain development may suggest new target areas in treatment., Highlights • Neuroimmunity plays a significant role in neuropathic pain pathogenesis neuropathic pain. • Immune mediators contribute to promotion, suppression or resolution of neuropathic pain. • Clinical studies in humans are lacking, most research available is pre-clinical or animal-based. • Evidence-based therapies for treatment of neuropathic pain demonstrate alteration in T cell phenotype and behavior post therapy.

T cells play an important role in the adaptive immune response to a variety of infections and cancers. Initiation of a T cell mediated immune response requires antigen recognition in a process termed MHC (Major Histocompatibility Complex) restriction. A T cell antigen is a composite structure made up of a peptide fragment bound within the antigen-binding groove of an MHC-encoded class I or class II molecule. Insight into the precise composition and biology of self and non-self immunopeptidomes is essential to harness T cell mediated immunity to prevent, treat, or cure infectious diseases and cancers. T cell antigen discovery is an arduous task! The pioneering work in the early 1990s has made large-scale T cell antigen discovery possible. Thus, advancements in mass spectrometry coupled with proteomics and genomics technologies make possible T cell antigen discovery with ease, accuracy, and sensitivity. Yet we have only begun to understand the breadth and the depth of self and non-self immunopeptidomes because the molecular biology of the cell continues to surprise us with new secrets directly related to the source, and the processing and presentation of MHC ligands. Focused on MHC class I molecules, this review, therefore, provides a brief historic account of T cell antigen discovery and, against a backdrop of key advances in molecular cell biologic processes, elaborates on how proteogenomics approaches have revolutionized the field. This article is protected by copyright. All rights reserved.

An epidemic of obesity over the past three decades increases the risk of chronic and infectious diseases for adults and children alike. Within the past few years, obesity has been shown to impair the adaptive immune response to infection through alterations in T cell functioning. Growing evidence suggests that perturbations in T cell metabolism drives this stunted immune response, stemming from nutrient, hormone and adipokine dysregulation in the obese. In this review, recent findings in the fields of obesity and T cell mediated immunity demonstrate a unique relationship between altered mechanisms of T cell metabolic homeostasis and plasticity of adaptive immune responses in the obese setting.

A T cell sleeper agent against stress Considerable changes in cellular metabolism occur when T cells transition from a resting to an activated state. One side effect of this process is an increase in reactive oxygen species (ROS). These molecules potentiate T cell receptor (TCR) signaling but can also result in detrimental oxidative stress (see the Perspective by Su and Dutta). Yue et al. describe one mechanism by which T cells can resolve this contradiction. Using mice with a T cell-specific deficiency in Schlafen 2 (SLFN2), they found that this protein binds to and protects transfer RNAs from oxidative stress-induced cleavage by the ribonuclease angiogenin. This process is downstream of ROS generation, which allows activated T cells to maintain protein synthesis despite the ROS that would otherwise inhibit translation. Science , this issue p. eaba4220 ; see also p. 683

A novel T cell–based ZIKV vaccine, encoding NS1 protein, confers protection against systemic infection., The causal association of Zika virus (ZIKV) with microcephaly, congenital malformations in infants, and Guillain-Barré syndrome in adults highlights the need for effective vaccines. Thus far, efforts to develop ZIKV vaccines have focused on the viral envelope. ZIKV NS1 as a vaccine immunogen has not been fully explored, although it can circumvent the risk of antibody-dependent enhancement of ZIKV infection, associated with envelope antibodies. Here, we describe a novel DNA vaccine encoding a secreted ZIKV NS1, that confers rapid protection from systemic ZIKV infection in immunocompetent mice. We identify novel NS1 T cell epitopes in vivo and show that functional NS1-specific T cell responses are critical for protection against ZIKV infection. We demonstrate that vaccine-induced anti-NS1 antibodies fail to confer protection in the absence of a functional T cell response. This highlights the importance of using NS1 as a target for T cell–based ZIKV vaccines.

International audience; Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV - notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T- and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions.

VITILIGO is considered an autoimmune depigmenting disease. There were many evidences suggested the role of T cell mediated immunity and cytokines in the pathogenesis of the disease. The study included 20 active vitiligo patients (group 1), 20 treated patients using narrow band ultraviolet radiation B (NBUVB) (group 2), and 20 healthy control of matching age and sex (group 3). IL- 17, IL-10, TGF- Bi levels in skin tissue were measured in the three groups using ELISA technique. The results showed a significant increase in IL- 17 and TGF-Bi while there was a significant decrease in IL-10 in active vitiligo patients compared to the control (P= 0.000). Following treatment using NB-UVB, the results showed a significant decrease in the level of both IL- 17 and TGF-Bi while there was a significant increase in IL-10 (P= 0.000) compared to active vitiligo group. These statistically significant results suggest the cell mediated immune role in the disease and successful treatment by the narrow band UVB that altered the cytokines toxic effect.

The novel PKC isoform, PKC-theta, is particularly enriched in T lymphocyte populations, serving a critical role in signal transduction after CD3/CD28 T cell receptor stimulation. PKC-theta is known to be involved in promoting T cell mediated immunity and has been implicated in other autoimmune diseases. We hypothesized that inhibition of this isoform would increase regulatory T cell phenotypes, promote an anti-inflammatory environment, and lead to delayed onset of type 1 diabetes in the NOD mouse model. A cell permeable pseudosubstrate peptide inhibitor was identified with potent suppression of IL-2 secretion at concentrations ≤15 μg in T cell enriched populations stimulated in vitro with CD3 and CD28 antibodies and a significant reduction in stimulated IL-2 secretion after 7 days of intraperitoneal treatment with 50 μg of pseudosubstrate inhibitor. Five-week-old prediabetic NOD mice were either treated daily with 50 μg of inhibitor or mock treated with saline for 4 weeks, then allowed to progress until 17 weeks of age. An 80% conversion to diabetes, based on IP glucose tolerance tests, was observed in saline mice compared to 30% conversion in inhibitor-treated mice, which correlated with a greater frequency of inflammation-free islets and islets with periinsulitis only in inhibitor-treated mice. Inhibitor-treated mice had increased frequencies of IL-10 secreting cells by ELISPOT, and increased Tregs in spleen at 17 weeks of age while reduced frequencies of IL-17+ CD4+ T cells. This study was repeated with a scrambled peptide control and later endpoint to determine if T1D would be prevented entirely. At 25 weeks of age a 66% conversion to diabetes was observed in scrambled peptide treated mice, while only 33% converted in the peptide treated. Our data demonstrate that PKC theta activation contributes to the progression of beta cell destruction in NOD mice, where inhibition of this isoform may confer an increase in protective regulatory T cell populations. Disclosure J.E. DiLisio: None. N. Mishkin: None. B. Podell: None. Funding National Institutes of Health (5K01OD016997 to B.P.); National Center for Advancing Translational Sciences (UL1TR001082 to B.P.)

The encapsulated fungus Cryptococcus neoformans (Cn) causes cryptococcal meningitis (CM). There are ~180,000 deaths per year worldwide attributed to CM, which is the most common cause of meningitis in adults with HIV in sub-Saharan Africa. HIV infection with advanced immunodeficiency is the most important predisposing risk factor for CM, highlighting the critical role that T cell mediated immunity plays in disease prevention. Numerous studies in the past decade demonstrate that antibody immunity also plays a role in resistance to CM, although its role has taken more time to establish. In mice, B cells reduce early dissemination from lungs to brain, and naive mouse IgM can enhance fungal containment in the lungs. In concert with these findings, human studies show that patients with CM have lower IgM memory B cell levels and/or different serological profiles than controls. In this article, we review recent data on the role that B cells and/or antibody-based immunity play in host defense against Cn and natural resistance to CM.

Recognition of antigenic peptides bound to major histocompatibility complex (MHC) proteins by αβ T cell receptors (TCRs) is a hallmark of T cell mediated immunity. Recent data suggest that variations in TCR binding geometry may influence T cell signaling, which could help explain outliers in relationships between physical parameters such as TCR-pMHC binding affinity and T cell function. Traditionally, TCR binding geometry has been described with simple descriptors such as the crossing angle, which quantifies what has become known as the TCR's diagonal binding mode. However, these descriptors often fail to reveal distinctions in binding geometry that are apparent through visual inspection. To provide a better framework for relating TCR structure to T cell function, we developed a comprehensive system for quantifying the geometries of how TCRs bind peptide/MHC complexes. We show that our system can discern differences not clearly revealed by more common methods. As an example of its potential to impact biology, we used it to reveal differences in how TCRs bind class I and class II peptide/MHC complexes, which we show allow the TCR to maximize access to and "read out" the peptide antigen. We anticipate our system will be of use in not only exploring these and other details of TCR-peptide/MHC binding interactions, but also addressing questions about how TCR binding geometry relates to T cell function, as well as modeling structural properties of class I and class II TCR-peptide/MHC complexes from sequence information. The system is available at https://tcr3d.ibbr.umd.edu/tcr_com or for download as a script.

Characterisation of the cellular immune response to schistosomiasis is well established for Schistosoma mansoni but a comprehensive description of T cell-mediated immune responses against S. japonicum infection is lacking. Accordingly, 20 CBA mice were infected with cercariae of S. japonicum and the immune response at different time points was determined. Mouse spleen and liver lymphocytes were isolated from the mice and stimulated with schistosomal adult worm antigen preparation (SWAP) and schistosomal soluble egg antigen (SEA). There was a relatively higher Th1 immune response to SWAP compared to SEA at the early phase of infection (up to week 5 post challenge). However, a Th2 immune response directed against SEA was dominant at week 6 post-infection, a time point when the highest IgG response against both SWAP and, especially, SEA was generated. The regulatory immune response was highest at the early phase of the immune response (up to week 5 post challenge) followed by a rapid decline at week 6-post infection. Before egg-laying, S. japonicum induced a regulatory T cell immune response which may limit the early Th1-mediated immune response that is believed to be protective in murine schistosomiasis. Following egg laying, the immune response was polarized to a Th2 immune response mainly directed against the eggs and this may contribute to parasite survival.

There is increasing enthusiasm and optimism that a vaccine could be developed that prevents infection rather than disease. In this article I discuss the fact that despite this optimism nothing has been produced so far that seems to have this capability, and moreover even the borderline between when infection ends and disease begins has not even been defined. To be effective such a vaccine, or at least the immunity it would generate, would have to work within the confines of the pulmonary physiological systems, which are complex. To date much of the emphasis here has turned away from T cell mediated immunity and towards establishing specific antibodies in the lungs. Here, I argue that with the exception of a possible exclusionary function, most claims of a protective role of antibody are completely over-blown. Finally, even if we had a potential "anti-infection" vaccine, how would we test and validate it?

Torque Teno viruses (TTVs) are small DNA viruses which are ubiquitous in nature. Recent reports indicate that swine torque teno viruses (TTSuVs) can act as primary pathogens or play a role in exacerbating co-infections. However, very little is known about the TTSuV host-viral interaction or how they so successfully establish chronic infections in the host. To determine whether the major viral proteins can modulate host immunity, recombinant TTSuV1 ORF1 and 2 proteins were expressed in a swine macrophage cell line (3D4/31). The differential expression of a panel of innate, adaptive, regulatory and inflammatory immune genes was studied by quantitative PCR; using cDNA samples collected at 6, 12, 24 and 48 hrs post-transfection. The ORF1 protein induced an early anti-viral response. However, at 6hrs post-transfection it also upregulated IL-10, PD-1 and SOCS-1, the suppressors of T cell mediated immunity. An ensuing diminishment of the early protective response was noted. The TTSuV1 ORF2 protein suppressed IFN-β and IL-13 responses but did not significantly influence anti-viral immunity otherwise. These findings indicate that the TTSuV1 ORF1 protein plays a significant but dual role in viral immunity.

Summary ParagraphThe field of gene therapy has been galvanized by the discovery of the highly efficient and adaptable site-specific nuclease system CRISPR/Cas9 from bacteria.1,2 Immunity against therapeutic gene vectors or gene-modifying cargo nullifies the effect of a possible curative treatment and may pose significant safety issues.3-5 Immunocompetent mice treated with CRISPR/Cas9-encoding vectors exhibit humoral and cellular immune responses against the Cas9 protein, that impact the efficacy of treatment and can cause tissue damage.5,6 Most applications aim to temporarily express the Cas9 nuclease in or deliver the protein directly into the target cell. Thus, a putative humoral antibody response may be negligible.5 However, intracellular protein degradation processes lead to peptide presentation of Cas9 fragments on the cellular surface of gene-edited cells that may be recognized by T cells. While a primary T cell response could be prevented or delayed, a pre-existing memory would have major impact. Here, we show the presence of a ubiquitous memory/effector T cell response directed towards the most popular Cas9 homolog from Streptococcus pyogenes (SpCas9) within healthy human subjects. We have characterized SpCas9-reactive memory/effector T cells (TEFF) within the CD4/CD8 compartments for multi-effector potency and lineage determination. Intriguingly, SpCas9-specific regulatory T cells (TREG) profoundly contribute to the pre-existing SpCas9-directed T cell immunity. The frequency of SpCas9-reactive TREG cells inversely correlates with the magnitude of the respective TEFF response. SpCas9-specific TREG may be harnessed to ensure the success of SpCas9-mediated gene therapy by combating undesired TEFF response in vivo. Furthermore, the equilibrium of Cas9-specific TEFF and TREG cells may have greater importance in Streptococcus pyogenes-associated diseases. Our results shed light on the T cell mediated immunity towards the much-praised gene scissor SpCas9 and offer a possible solution to overcome the problem of pre-existing immunity.

In the last few years, new drugs able to inhibit the B-cell receptor (BCR) pathway have been approved by the US and European drug control agencies for the treatment of chronic lymphocytic leukemia (CLL) and some indolent B lymphomas. Among them, ibrutinib and idelalisib, respectively, target the

Chemokines are small (~8-14 kDa) structurally-related chemotactic cytokines that regulate cell trafficking through interactions with specific seven-trans membrane, G protein-coupled receptors (GPCRs). One of the important features of G protein-coupled receptors (GPCRs) is their ability to transmit diverse signaling cascades upon binding different ligands. The current review focuses on the interplay between three ligands: CXCL9, CXCL10 and CXCL11 binding the same receptor (CXCR3) on CD4+ T cells, yet direct different signaling cascades to shape T cell mediated immunity. The review brings about a new concept regarding the biological activities of chemokines in shaping CD4+ T cell immunity, and also a new approach for applying chemokine based therapy of autoimmune diseases.

Trabajo patrocinado por: Fondo Mejicano para Conservacion de la Naturaleza. Proyecto PIE 2012 A-P-C-IGSI-12-12 Gobierno de Extremadura. CONACYT (I010/176/2012) y becas PO10014 y RE12002 Gobierno de Extremadura. Direccion General de Vida Silvestre. SGPA/ DGVS/08559/11

Nitric oxide (NO) is a key messenger in the pathogenesis of inflammation, linking innate and adaptive immunity. By targeting signaling molecules, NO from inducible NO synthase (iNOS) and endothelial (e)NOS affects T helper cell differentiation and the effector functions of T lymphocytes, and is a potential target for therapeutic manipulation. In this review we discuss the regulatory actions exerted by NO on T cell functions, focusing on S-nitrosylation as an important post-translational modification by which NO acts as a signaling molecule during T cell-mediated immunity. We also present recent findings showing novel mechanisms through which NO regulates the activation of human T cells, and consider their potential in strategies to treat tumoral, allergic, and autoimmune diseases.

Intralesional (IL) injection of Rose Bengal (PV-10) induces regression of injected and uninjected lesions in several murine tumor models. In this study, we investigated the anti-tumor response of combining IL PV-10 with blockade of the PD-1 / PD-L1 pathway and the role of immune cell populations in eliciting this response. To investigate the role of T cell subsets in mediating an immune response, B16 or M05 melanoma-bearing mice received combination therapy as well as CD8+, CD4+, or CD25+ depleting antibodies. Tumor growth was measured. T cells were collected from spleens or tumors, and phenotype, activation markers, and reactivity were measured. Splenocytes from mice treated with combination therapy had increased OVA antigen-specific CD8+ T cells in M05-tumor-bearing mice. Depletion of CD4+ T cells or regulatory T cells (Tregs) in combination with IL PV-10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect. Treatment with CD8+ depleting antibody abrogated anti-tumor immunity. These results support a clinical study for the safety and anti-tumor immune responses with combination therapy of IL PV-10 and PD-1/PD-L1 blockade.

Immunobiotic lactic acid bacteria have become an interesting alternative for the prevention of respiratory infections. Previously, we demonstrated that the nasal administration of Lactobacillus rhamnosus CRL1505, during repletion of malnourished mice, resulted in diminished susceptibility to the challenge with the respiratory pathogen Streptococcus pneumoniae. Considering the known alterations induced by malnutrition on T lymphocytes and the importance of this cell population on the protection against respiratory pathogens, we aimed to study the effect of L. Rhamnosus CRL1505 nasal administration on the recovery of T cell-mediated defences against pneumococcal infection in malnourished mice under nutritional recovery. Malnourished mice received a balanced conventional diet (BCD) for seven days or BCD for seven days with nasal L. Rhamnosus CRL1505 supplementation during last two days of the treatment. After the treatments mice were infected with S. Pneumoniae. Flow cytometry studies were carried out in bone marrow, thymus, spleen and lung to study T cells, and Th1/Th2 cytokine profiles were determined in broncho-alveolar lavages and serum. The administration of CRL1505 strain to malnourished mice under recovery reduced quantitative and qualitative alterations of CD4+ T cells in the bone marrow, thymus, spleen and lung induced by malnutrition. In addition, CRL1505 treatment augmented Th2- cytokines (interleukin 10 and 4) in respiratory and systemic compartments after pneumococcal infection. These results show that modulation of CD4+ T lymphocytes induced by L. Rhamnosus CRL1505 has an important role in the beneficial effect induced by this strain on the recovery of malnourished mice. These data also indicate that nasally administered L. Rhamnosus CRL1505 may represent a non-invasive alternative to modulate and improve the T cell-mediated immunity against respiratory pathogens in immunocompromised malnourished hosts. Fil: Barbieri, Natalia Paola del Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina. Universidad Nacional de Chilecito; Argentina Fil: Herrera, Héctor Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina Fil: Salva, Maria Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina Fil: Villena, Julio Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina Fil: Alvarez, Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucuman. Centro de Referencia Para Lactobacilos; Argentina. Universidad Nacional de Tucumán; Argentina

Hepatotropic viruses such as hepatitis C virus cause life-threatening chronic liver infections in millions of people worldwide. Targeted in vivo antigen-delivery to cross-presenting dendritic cells (DCs) has proven to be extraordinarily efficient in stimulating antigen-specific T cell responses. To determine whether this approach would as well be suitable to induce local antiviral effector T cells in the liver we compared different vaccine formulations based on either the targeting of DEC-205 or TLR2/6 on cross-presenting DCs or formulations not involving in vivo DC targeting. As read-outs we used in vivo hepatotropic adenovirus challenge, histology and automated multidimensional fluorescence microscopy (MELC). We show that targeted in vivo antigen delivery to cross-presenting DCs is highly effective in inducing antiviral CTLs capable of eliminating virus-infected hepatocytes, while control vaccine formulation not involving DC targeting failed to induce immunity against hepatotropic virus. Moreover, we observed distinct patterns of CD8+ T cell interaction with virus-infected and apoptotic hepatocytes in the two DC-targeting groups suggesting that the different vaccine formulations may stimulate distinct types of effector functions. Our findings represent an important step toward the future development of vaccines against hepatotropic viruses and the treatment of patients with hepatic virus infection after liver transplantation to avoid reinfection.

T cell-mediated immunity is central to the pathogenesis of autoimmune diseases, and is a target in the development of alternative therapeutic strategies with reduced adverse effects on other cell types and organs. Protein kinase C (PKC) is a family of serine/threonine kinases, with knockout of the PKCθ isoform in mice resulting in defective T cell activation. However, the effects of selective inhibition of PKCθ by small-molecule compounds on T cell signaling are still unknown. Here, we evaluated the effect of the novel PKCθ inhibitor AS2521780 on T cell activation and joint inflammation in a rat model of arthritis. AS2521780 exerted potent inhibition of recombinant human PKCθ enzyme activity (IC50=0.48 nM), which was more than 30-fold higher than that of other PKC isoforms. Further, AS2521780 exerted little or no inhibition on other protein kinases. AS2521780 suppressed CD3/CD28-induced Interleukin-2 (IL-2) gene transcription in Jurkat T cells and proliferation of human primary T cells. AS2521780 also suppressed concanavalin A-induced cytokine production by rat splenocytes and monkey peripheral blood mononuclear cells with similar potency. Moreover, AS2521780 significantly reduced paw swelling in a dose-dependent manner in a rat model of adjuvant-induced arthritis. These results indicate that PKCθ is an attractive drug target and AS2521780 is a potential immunosuppressant for T cell-mediated autoimmune diseases.