Search

The body's immune response plays a critical role in defending against external or foreign antigens while also preserving tolerance to self‐antigens. This equilibrium, referred to as immune homeostasis, is paramount for overall health. The regulatory mechanisms governing the maintenance of this delicate immune balance are notably complex. It is currently accepted that immune tolerance is a dynamic outcome regulated by multiple factors, including central and peripheral mechanisms. Its induction or elimination plays a significant role in autoimmune diseases, organ transplantation, and cancer therapy, markedly impacting various major diseases in modern clinical practice. Overall, our current understanding of immune tolerance is still very limited. In this review article, we summarized the main mechanisms that have been known to mediate immune tolerance so far, including endogenous immune tolerance, adaptive immune tolerance, other immune tolerance mechanisms, and the homeostasis of immune tolerance, identified the key factors that regulate immune tolerance, and provided new clues for immune system recovery in many autoimmune diseases, organ transplantation, and tumor therapy. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is the most frequent immune‐mediated neurological disorder, characterized by fluctuating muscle weakness. Specific recognition of self‐antigens by T‐cell receptors (TCRs) and B‐cell receptors (BCRs), coupled with T–B cell interactions, activates B cells to produce autoantibodies, which are critical for the initiation and perpetuation of MG. The immune repertoire comprises all functionally diverse T and B cells at a specific time point in an individual, reflecting the essence of immune selectivity. By sequencing the nucleotide sequences of TCRs and BCRs, it is possible to track individual T‐ and B‐cell clones. This review delves into the generation of autoreactive TCRs and BCRs in MG and comprehensively examines the applications of immune repertoire sequencing in understanding disease pathogenesis, developing diagnostic and prognostic markers and informing targeted therapies. We also discuss the current limitations and future potential of this approach. [ABSTRACT FROM AUTHOR]

T lymphocytes play a vital role in the immune‐inflammatory response following a stroke. However, the specific mechanisms behind the contrasting functions of T cells in the brain and peripheral tissues after a stroke remain unclear and require further investigation. T‐cell receptors (TCRs) are essential in controlling how T lymphocytes develop and become active. This study aims to gain a deeper understanding of the biological function of T lymphocytes by analyzing the TCR repertoire in patients who have experienced an acute ischemic stroke (AIS). High‐throughput TCR sequencing was conducted on peripheral blood samples from 25 AIS patients and 10 healthy controls. We compared the percentage of T cells and the characteristics of the TCR repertoire, specifically focusing on the recombination of V(D)J gene fragments and the diversity of the complementarity determining region 3 (CDR3) of the Vβ gene. Additionally, this study analyzed the potential biological significance of the skewed TCR repertoire in AIS patients. In patients with AIS, the proportion of circulating lymphocytes (LY%) decreased while the systemic immune‐inflammatory index (SII) increased compared to healthy controls. The average number of TCR read pairs decreased, corresponding with the presence of lymphopenia. However, the recombination of V(D)J gene fragments, the number of CDR3 clonotypes, and the diversity of CDR3 was elevated in the peripheral blood of AIS patients. Furthermore, the increased number of CDR3 amino acid or nucleotide clonotypes was negatively correlated with neurologic deficits but positively correlated with AIS patients' systemic immune condition and functional outcomes. Our findings suggest that both immunosuppression and enhanced antigen‐specific T‐cell response may exist in the periphery of the AIS patients. Further investigation into the mechanisms underlying these opposing changes may lead to the discovery of novel targets to reverse immunosuppression or mitigate the detrimental effects of T cells in the lesioned brain of AIS patients. [ABSTRACT FROM AUTHOR]

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T‐cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0–16 years) with blood culture‐proven bacterial sepsis caused by HMBPP‐positive Escherichia coli or by HMBPP‐negative Staphylococcus aureus or by HMBPP‐negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal‐derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens. [ABSTRACT FROM AUTHOR]

Unsaturated fatty acids (UFA) are crucial for T‐cell effector functions, as they can affect the growth, differentiation, survival, and function of T cells. Nonetheless, the mechanisms by which UFA affects T‐cell behavior are ill‐defined. Therefore, we analyzed the processing of oleic acid, a prominent UFA abundantly present in blood, adipocytes, and the fat pads surrounding lymph nodes, in CD4+ T cells. We found that exogenous oleic acid increases proliferation and enhances the calcium flux response upon CD3/CD28 activation. By using a variety of techniques, we found that the incorporation of oleic acid into membrane lipids, rather than regulation of cellular metabolism or TCR expression, is essential for its effects on CD4+ T cells. These results provide novel insights into the mechanism through which exogenous oleic acid enhances CD4+ T‐cell function. [ABSTRACT FROM AUTHOR]

The size and condition of the peripheral CD4 T cell population determine the capacity of the immune response. Under homeostatic conditions, the size of the peripheral CD4 T cell population is maintained through turnover and survival. However, the underlying mechanisms remain inadequately understood. Here, we observed a significant decrease in the percentage of CD4 T cells in the periphery following the targeted deletion of the Paxbp1 gene in mouse T cells. In the absence of Paxbp1, naïve CD4 T cells displayed reduced surface interleukin‐7 receptor levels and a decreased capacity to respond to survival signals mediated by interleukin‐7. In addition, naïve CD4 T cells deficient in Paxbp1 demonstrated impaired T cell antigen receptor signalling, compromised cell cycle entry, decreased proliferation, and increased apoptosis following stimulation, all of which contributed to the reduction in the number of peripheral CD4 T cells. Therefore, our study highlights the indispensable role of Paxbp1 in maintaining peripheral CD4 T cell homeostasis. [ABSTRACT FROM AUTHOR]

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

Objectives: Recent immunologic study of the adaptive immune repertoire in the subglottic airway demonstrated high‐frequency T cell clones that do not overlap between individuals. However, the anatomic distribution and antigenic target of the T cell repertoire in the proximal airway mucosa remain unresolved. Methods: Single‐cell RNA sequencing of matched scar and unaffected mucosa from idiopathic subglottic stenosis patients (iSGS, n = 32) was performed and compared with airway mucosa from healthy controls (n = 10). T cell receptor (TCR) sequences were interrogated via similarity network analysis to explore antigenic targets using the published algorithm: Grouping of Lymphocyte Interactions by Paratope Hotspots (GLIPH2). Results: The mucosal T cell repertoire in healthy control airways consisted of highly expressed T cell clones conserved across anatomic subsites (trachea, bronchi, bronchioles, and lung). In iSGS, high‐frequency clones were equally represented in both scar and adjacent non‐scar tissue. Significant differences in repertoire structure between iSGS scar and unaffected mucosa was observed, driven by unique low‐frequency clones. GLIPH2 results suggest low‐frequency clones share targets between multiple iSGS patients. Conclusion: Healthy airway mucosa has a highly conserved T cell repertoire across multiple anatomic subsites. Similarly, iSGS patients have highly expressed T cell clones present in both scar and unaffected mucosa. iSGS airway scar possesses an abundance of less highly expanded clones with predicted antigen targets shared between patients. Interrogation of these shared motifs suggests abundant adaptive immunity to viral targets in iSGS airway scar. These results provide insight into disease pathogenesis and illuminate new treatment strategies in iSGS. Level of Evidence: NA Laryngoscope, 134:3245–3252, 2024 [ABSTRACT FROM AUTHOR]

Myocarditis has emerged as a rare but lethal immune checkpoint inhibitor (ICI)‐associated toxicity. However, the exact mechanism and the specific therapeutic targets remain underexplored. In this study, we aim to characterise the transcriptomic profiles based on single‐cell RNA sequencing from ICI‐related myocarditis. Peripheral blood mononuclear cell (PBMC) samples were collected from four groups for single‐cell RNA sequencing: (1) patients with newly diagnosed lung squamous cell carcinoma before treatment (Control Group); (2) patients with lung squamous cell carcinoma with PD‐1 inhibitor therapy who did not develop myocarditis (PD‐1 Group); (3) patients during fulminant ICI‐related myocarditis onset (Myocarditis Group); and (4) Patients with fulminant ICI‐related myocarditis during disease remission (Recovery Group). Subcluster determination, functional analysis, single‐cell trajectory and cell–cell interaction analysis were performed after scRNA‐seq. Bulk‐RNA sequencing was performed for further validation. Our results revealed the diversity of cellular populations in ICI‐related myocarditis, marked by their distinct transcriptional profiles and biological functions. Monocytes, NKs as well as B cells contribute to the regulation of innate immunity and inflammation in ICI‐related myocarditis. With integrated analysis of scRNA‐seq and bulk sequencing, we identified S100A protein family as a potential serum marker for ICI‐related myocarditis. Our study has created a cell atlas of PBMC during ICI‐related myocarditis, which would shed light on the pathophysiological mechanism and potential therapeutic targets of ICI‐related myocarditis in continuous exploration. [ABSTRACT FROM AUTHOR]

Deciphering cellular interactions is essential to both understand the mechanisms underlying a broad range of human diseases, but also to manipulate therapies targeting these diseases. Here, the formation of cell doublets resulting from specific membrane ligand‐receptor interactions is discovered. Based on this phenomenon, the study developed DoubletSeeker, a novel high‐throughput method for the reliable identification of ligand‐receptor interactions. The study shows that DoubletSeeker can accurately identify T cell receptor (TCR)‐antigen interactions with high sensitivity and specificity. Notably, DoubletSeeker effectively captured paired TCR‐peptide major histocompatibility complex (pMHC) information during a highly complex library‐on‐library screening and successfully identified three mutant TCRs that specifically recognize the MART‐1 epitope. In turn, DoubletSeeker can act as an antigen discovery platform that allows for the development of novel immunotherapy targets, making it valuable for investigating fundamental tumor immunology. [ABSTRACT FROM AUTHOR]

Objectives: Recent translational scientific efforts in subglottic stenosis (SGS) support a disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. Given the observed immune cell infiltrate in SGS, we sought to test the hypothesis that SGS cases possessed a low diversity (highly clonal) adaptive immune response when compared with healthy controls. Methods: Single cell RNA sequencing (scRNA‐seq) of subglottic mucosal scar in iSGS (n = 24), iLTS (n = 8), and healthy controls (n = 7) was performed. T cell receptor (TCR) sequences were extracted, analyzed, and used to construct repertoire structure, compare diversity, interrogate overlap, and define antigenic targets using the Immunarch bioinformatics pipeline. Results: The proximal airway mucosa in health and disease are equally diverse via Hill framework quantitation (iSGS vs. iLTS vs. Control, p > 0.05). Repertoires do not significantly overlap between individuals (Morisita <0.02). Among iSGS patients, clonality of the TCR repertoire is driven by CD8+ T cells, and iSGS patients possess numerous TCRs targeting viral and intercellular pathogens. High frequency clonotypes do not map to known targets in public datasets. Conclusion: SGS cases do not possess a lower diversity adaptive immune infiltrate when compared with healthy controls. Interestingly, the TCR repertoire in both health and disease contains a restricted number of high frequency clonotypes that do not significantly overlap between individuals. The target of the high frequency clonotypes in health and disease remain unresolved. Level of Evidence: NA Laryngoscope, 134:1757–1764, 2024 [ABSTRACT FROM AUTHOR]

HLA antigen presentation and T‐cell mediated immunity are critical to control acute viral infection such as COVID‐19 caused by SARS‐CoV‐2. Recent data suggest that both the depth of peptide presentation and the breadth of the T‐cell repertoire are associated with disease outcome. It has also been shown that unexposed subjects can develop strong T‐cell responses against SARS‐CoV‐2 due to heterologous immunity. In this study, we explored the anti‐SARS‐CoV‐2 T‐cell repertoire by analyzing previously published T‐cell receptor (TCR) CDR3β immunosequencing data in a cohort of 116 healthy donors and in the context of immune reconstitution after allogeneic hematopoietic stem cell transplantation in 116 recipients collected during the pre‐COVID‐19 era. For this, 143,310 publicly available SARS‐CoV‐2 specific T‐cell sequences were investigated among the 3.5 million clonotypes in the cohort. We also performed HLA class I peptide binding predictions using the reference proteome of the virus and high resolution genotyping data in these patients. We could demonstrate that individuals are fully equipped at the genetic level to recognize SARS‐CoV‐2. This is evidenced by the 5% median cumulative frequency of clonotypes having their sequence matched to a SARS‐CoV‐2 specific T‐cell. In addition, any combination of HLA class I variants in this cohort is associated with a broad capacity of presenting hundreds of SARS‐CoV‐2 derived peptides. These results could be explained by heterologous immunity and random somatic TCR recombination. We speculate that these observations could explain the efficacy of the specific immune response against SARS‐CoV‐2 in individuals without risk factors of immunodeficiency and infected prior to vaccination. [ABSTRACT FROM AUTHOR]

Summary: Since their discovery, CD4+CD25hiFOXP3hi regulatory T cells (Tregs) have been firmly established as a critical cell type for regulating immune homeostasis through a plethora of mechanisms. Due to their immunoregulatory power, delivery of polyclonal Tregs has been explored as a therapy to dampen inflammation in the settings of transplantation and autoimmunity. Evidence shows that Treg therapy is safe and well‐tolerated, but efficacy remains undefined and could be limited by poor persistence in vivo and lack of antigen specificity. With the advent of new genetic engineering tools, it is now possible to create bespoke "designer" Tregs that not only overcome possible limitations of polyclonal Tregs but also introduce new features. Here, we review the development of designer Tregs through the perspective of three 'eras': (1) the era of FOXP3 engineering, in which breakthroughs in the biological understanding of this transcription factor enabled the conversion of conventional T cells to Tregs; (2) the antigen‐specificity era, in which transgenic T‐cell receptors and chimeric antigen receptors were introduced to create more potent and directed Treg therapies; and (3) the current era, which is harnessing advanced genome‐editing techniques to introduce and refine existing and new engineering approaches. The year 2022 marked the entry of "designer" Tregs into the clinic, with exciting potential for application and efficacy in a wide variety of immune‐mediated diseases. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic esophagitis (EoE) involves a chronic immune‐mediated response to dietary antigens. Recent work identifies T‐cell clonality in children with EoE, however, it is unknown whether this is true in adults or whether there is a restricted food‐specific T‐cell repertoire. We sought to confirm T‐cell receptor (TCR) clonality in EoE and assess for differences with specific food triggers. Methods: Bulk TCR sequencing was performed on mRNA isolated from esophageal biopsies obtained from adults and children with EoE (n = 15) who had food triggers confirmed by endoscopic evaluation. Non‐EoE adult and pediatric controls (n = 10) were included. Differences in TCR clonality by disease and treatment status were assessed. Shared and similar V‐J‐CDR3s were assessed based on specific food triggers. Results: Active EoE biopsies from children but not adults displayed decreased unique TCRα/β clonotypes and increased relative abundance of TCRs comprising >1% of the total compared to non‐EoE controls and paired inactive EoE samples. Among patients in which baseline, post diet elimination, and food trigger reintroduction samples (n = 6) were obtained, we observed ~1% of TCRs were shared only between pre‐diet elimination and trigger reintroduction. Patients with a shared EoE trigger (milk) had a greater degree of shared and similar TCRs compared to patients with differing triggers (seafood, wheat, egg, soy). Conclusion: We confirmed relative clonality in children but not adults with active EoE and identified potential food‐specific TCRs, particularly for milk‐triggered EoE. Further studies are needed to better identify the broad TCR repertoire relevant to food triggers. [ABSTRACT FROM AUTHOR]

The search for the relationships between CDR3 TCR sequences and epitopes or MHC types is a challenging task in modern immunology. We propose a new approach to develop the classification models of structure–activity relationships (SAR) using molecular fragment descriptors MNA (Multilevel Neighbourhoods of Atoms) to represent CDR3 TCR sequences and the naïve Bayes classifier algorithm. We have created the freely available TCR‐Pred web application (http://way2drug.com/TCR-pred/) to predict the interactions between α chain CDR3 TCR sequences and 116 epitopes or 25 MHC types, as well as the interactions between β chain CDR3 TCR sequences and 202 epitopes or 28 MHC types. The TCR‐Pred web application is based on the data (more 250 000 unique CDR3 TCR sequences) from VDJdb, McPAS‐TCR, and IEDB databases and the proposed approach. The average AUC values of the prediction accuracy calculated using a 20‐fold cross‐validation procedure varies from 0.857 to 0.884. The created web application may be useful in studies related with T‐cell profiling based on CDR3 TCR sequences. [ABSTRACT FROM AUTHOR]

While γδ T cells are present virtually in all vertebrates, there is a remarkable lack of conservation of the TRG and TRD loci underlying the generation of the γδ T cell receptor (TCR), which is associated with the generation of species-specific γδ T cells. A prominent example is the human phosphoantigen-reactive Vγ9Vd2 T cell subset that is absent in mice. Murine γδ thymocyte cells were among the first immune cells identified to follow a wave-based layered development during embryonic and early life, and since this initial observation, in-depth insight has been obtained in their thymic ontogeny. By contrast, less is known about the development of human γδ T cells, especially regarding the generation of γδ thymocyte waves. Here, after providing an overview of thymic γδ wave generation in several vertebrate classes, we review the evidence for γδ waves in the human fetal thymus, where single-cell technologies have allowed the breakdown of human γδ thymocytes into functional waves with important TCR associations. Finally, we discuss the possible mechanisms contributing to the generation of waves of γδ thymocytes and their possible significance in the periphery. [ABSTRACT FROM AUTHOR]

Acquired aplastic anaemia (AA) is an autoimmune bone marrow failure disease resulting from a cytotoxic T-cell-mediated attack on haematopoietic stem and progenitor cells (HSPCs). Despite significant progress in understanding the T-cell repertoire alterations in AA, identifying specific pathogenic T cells in AA patients has remained elusive, primarily due to the unknown antigenic targets of the autoimmune attack. In this review, we will synthesize findings from several decades of research to critically evaluate the current knowledge on T-cell repertoires in AA. We will highlight new insights gained from recent in vitro studies of candidate autoreactive T cells isolated from AA patients and will discuss efforts to identify shared T-cell clonotypes in AA. Finally, we will discuss emerging evidence on the potential T-cell cross-reactivity between HSPC and common viral epitopes that may contribute to the development of AA in some patients. We conclude by highlighting the areas of consensus and limitations, as well as the ongoing uncertainties, and we identify promising directions for future research in the field., (© 2025 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

However, only two patients with TCR SP + sp T-LGLL had mild splenomegaly and only one patient with TCR SP + sp T-LGLL presented with thrombocytopenia. Keywords: immunophenotypes; pure red cell aplasia; STAT3; T-cell large granular leukaemia; TCR EN immunophenotypes pure red cell aplasia STAT3 T-cell large granular leukaemia TCR e18 e22 5 07/18/22 20220715 NES 220715 Large granular lymphocyte leukaemia (LGLL) is a rare lymphoproliferative disease with three recognised subgroups including T-cell large granular lymphocytic leukaemia (T-LGLL), chronic natural killer (NK) cell lymphocytosis, and NK cell leukaemia.1 Approximately 85% of LGLLs is T-LGLL, which is caused by persistence of increased large granular cells in the peripheral blood, bone marrow, spleen and liver resulting in cytopenia, autoimmune diseases and so on. TCR SP + sp T-LGLL, 70.0% vs. 83.3%, I p i = 0.664; CD4 SP - sp TCR SP + sp T-LGLL vs. Furthermore, none of the patients with TCR SP + sp T-LGLL had PRCA, indicating TCR SP + sp and TCR SP + sp T-LGLL may have different clinical manifestations. [Extracted from the article]

Autoimmune diseases are characterized by dysfunctional immune systems that misrecognize self as non‐self and cause tissue destruction. Several cell types have been implicated in triggering and sustaining disease. Due to a strong association of major histocompatibility complex II (MHC‐II) proteins with various autoimmune diseases, CD4+ T lymphocytes have been thoroughly investigated for their roles in dictating disease course. CD4+ T cell activation is a coordinated process that requires three distinct signals: Signal 1, which is mediated by antigen recognition on MHC‐II molecules; Signal 2, which boosts signal 1 in a costimulatory manner; and Signal 3, which helps to differentiate the activated cells into functionally relevant subsets. These signals are disrupted during autoimmunity and prompt CD4+ T cells to break tolerance. Herein, we review our current understanding of how each of the three signals plays a role in three different autoimmune diseases and highlight the genetic polymorphisms that predispose individuals to autoimmunity. We also discuss the drawbacks of existing therapies and how they can be addressed to achieve lasting tolerance in patients. [ABSTRACT FROM AUTHOR]

The nonpolymorphic class Ib molecule, HLA‐E, primarily presents peptides from HLA class Ia leader peptides, providing an inhibitory signal to NK cells via CD94/NKG2 interactions. Although peptides of pathogenic origin can also be presented by HLA‐E to T cells, the molecular basis underpinning their role in antigen surveillance is largely unknown. Here, we solved a co‐complex crystal structure of a TCR with an HLA‐E presented peptide (pHLA‐E) from bacterial (Mycobacterium tuberculosis) origin, and the first TCR‐pHLA‐E complex with a noncanonically presented peptide from viral (HIV) origin. The structures provided a molecular foundation to develop a novel method to introduce cysteine traps using non‐natural amino acid chemistry that stabilized pHLA‐E complexes while maintaining native interface contacts between the TCRs and different pHLA‐E complexes. These pHLA‐E monomers could be used to isolate pHLA‐E‐specific T cells, with obvious utility for studying pHLA‐E restricted T cells, and for the identification of putative therapeutic TCRs. [ABSTRACT FROM AUTHOR]

The avidity of TCRs for peptide‐major histocompatibility complexes (pMHCs) is a governing factor in how T cells respond to antigen. TCR avidity is generally linked to T‐cell functionality and there is growing evidence for distinct roles of low and high avidity T cells in different phases of immune responses. While physiological immune responses and many therapeutic T‐cell products targeting infections or cancers consist of polyclonal T‐cell populations with a wide range of individual avidities, the role of T‐cell avidity is usually investigated only in monoclonal experimental settings. In this report, we induced polyclonal T‐cell responses with a wide range of avidities toward a model epitope by altered peptide ligands, and benchmarked global avidity of physiological polyclonal populations by investigation of TCR‐pMHC koff‐rates. We then investigated how varying sizes and avidities of monoclonal subpopulations translate into global koff‐rates. Global koff‐rates integrate subclonal avidities in a predictably weighted manner and robustly correlate with the functionality of murine polyclonal T‐cell populations in vitro and in vivo. Surveying the full avidity spectrum is essential to accurately assess polyclonal immune responses and inform the design of polyclonal T‐cell therapeutics. [ABSTRACT FROM AUTHOR]

This introductory article makes a critical estimation of the impact of pandemics on the Global South consumer's well‐being. Our paper moves beyond the concerns of the other papers of this Special Issue. Instead, we focus on the issues of the vulnerable, marginal, and subaltern consumers of the Global South—experiences and anxieties, distinct from those of more "modern," capitalized, industrialized, democratized, and economically liberated Global North consumers. We offer the North–South comparisons across national lines or from block to block that bring in a series of promising directions and new currents in the critical, interdisciplinary studies of consumer affairs. Primary perspectives and associated topics for future agenda impacting TCR highlighted are (i) socio‐economic inequalities and injustices, (ii) environmental injustice and sustainable future. We finally suggest an innovative research paradigm, "altruistic‐activist consumer research," to address the concerns and impact the well‐being of marginal consumers from the Global South. [ABSTRACT FROM AUTHOR]

Regulatory T cells (Tregs) are essential for the inhibition of immunity and the maintenance of tissue homeostasis. Signals from the T‐cell antigen receptor (TCR) are critical for early Treg development, their expansion, and inhibitory activity. Although TCR‐engaged activation of the paracaspase MALT1 is important for these Treg activities, the MALT1 effector pathways in Tregs remain ill‐defined. Here, we demonstrate that MALT1 protease activity controls the TCR‐induced upregulation of the transcription factor MYC and the subsequent expression of MYC target genes in Tregs. These mechanisms are important for Treg‐intrinsic mitochondrial function, optimal respiratory capacity, and homeostatic Treg proliferation. Consistently, conditional deletion of Myc in Tregs results similar to MALT1 inactivation in a lethal autoimmune inflammatory syndrome. Together, these results identify a MALT1 protease‐mediated link between TCR signaling in Tregs and MYC control that coordinates metabolism and Treg expansion for the maintenance of immune homeostasis. [ABSTRACT FROM AUTHOR]

Tumor‐infiltrating lymphocytes (TILs) are a potent source for obtaining tumor‐reactive T cell receptors (TCRs). Although comprehensive methods to analyze the TCR repertoire in TILs have been reported, the evaluation system for TCR‐reactivity to endogenously expressed antigen in tumor cells remains laborious and time consuming. Consequently, very limited numbers of TCRs in TILs have been analyzed for their reactivity to tumor cells. In this study, we developed an efficient evaluation system for TCR function designated c‐FIT (comprehensive functional investigation of TCRs) to analyze TCR reactivity. The c‐FIT system enabled us to analyze up to 90 TCRs for their reactivity to tumor cells by a single assay within a month. Using c‐FIT, we analyzed 70 TCRs of CD8+ TILs derived from two breast cancer patients and obtained 23 TCRs that reacted to tumor cells. Surprisingly, although two TCRs were HLA class I‐restricted, the remaining 21 TCRs were non‐HLA‐restricted. Thus, c‐FIT can be applied for monitoring multiple conventional and unconventional antigen‐specific killer T cells in TILs, leading to the development of new designs for more effective T‐cell‐based immunotherapies. [ABSTRACT FROM AUTHOR]

CD4+CD8+ double‐positive thymocytes give rise to both conventional TCRαβ+ T cells and invariant natural killer T cells (iNKT cells), but these two kinds of cells display different characteristics. The molecular mechanism underlying iNKT cell lineage development and function acquisition remain to be elucidated. We show that the loss of chromatin assembly factor 1B (CHAF1b) maintains the normal development of conventional TCRαβ+ T cells but severely impairs early development of iNKT cells. This dysregulation is accompanied by the impairment in chromatin activation and gene transcription at Vα14‐Jα18 locus. Notably, ectopic expression of a Vα14‐Jα18 TCR rescues Chaf1b‐deficient iNKT cell developmental defects. Moreover, cytokine secretion and antitumor activity are substantially maintained in Vα14‐Jα18 TCR transgene‐rescued Chaf1b‐deficient iNKT cells. Our study identifies CHAF1b as a critical factor that controls the early development but not function acquisition of iNKT cells via lineage‐ and stage‐specific regulation. [ABSTRACT FROM AUTHOR]

Non-TCR-like antibodies cannot bind biotinylated target p/MHC and signals are absent or weak (top, right), whereas the TCR-like antibody binds only to biotinylated target p/MHC, generating obvious signals (bottom, right). Keywords: ISAAC; TCR; TCR-like antibody; tumor immunotherapy EN ISAAC TCR TCR-like antibody tumor immunotherapy 1850 1853 4 07/05/21 20210701 NES 210701 Generation of TCR-like monoclonal antibodies using conventional methods is markedly laborious and inefficient. In contrast, with the blockade, eight (90%) of nine cells with FI >= 130 produced TCR-like antibodies, and none of the nine cells with FI <130 produced TCR-like antibodies (Fig. This study demonstrates that ISAAC with blocking procedure is useful to generate TCR-like antibodies recognizing the EBV-derived BRLF1 peptide presented on HLA-A24 molecule (BRLF1p/HLA-A24). [Extracted from the article]

Although T‐cell receptors (TCRs) are related to the progression of breast cancer (BC), their prognostic values remain unclear. We downloaded the messenger RNA (mRNA) profiles and corresponding clinical information of 1413 BC patients from the Cancer Genome Atlas and Gene Expression Omnibus database, respectively. The different expression analysis of 104 TCRs in BC samples was performed, and the consensus clustering based on 104 TCRs was performed by using the K‐mean method of R language. Univariate cox regression analysis was used to screen TCRs significantly associated with the prognosis of BC, and LASSO Cox analysis was applied to optimize key TCRs. The risk score was calculated using the prognostic model constructed based on six optimal TCRs, and multivariate Cox regression analysis was used to determine whether it was an independent prognostic signature. Finally, the nomogram was constructed to predict the overall survival of BC patients. Six optimal TCRs (ZAP70, GRAP2, NFKBIE, IFNG, NFKBIA, and PAK5), which were favorable for the prognosis of BC patients, were screened. Risk score could reliably predict the prognosis of BC patients as an independent prognostic signature. In addition, when bringing into two independent prognostic signatures, age and risk score, the nomogram model could better predict the overall survival of BC patients. Our results suggested that the poor prognosis of BC patients with high risk might be due to an immunosuppressive microenvironment. In summary, a prognostic risk model based on six TCRs was established and could efficiently predict the prognosis of BC patients. [ABSTRACT FROM AUTHOR]

A T‐cell receptor (TCR) with optimal avidity to a tumor antigen can be used to redirect T cells to eradicate cancer cells via adoptive cell transfer. Cancer testis antigens (CTAs) are attractive targets because they are expressed in the testis, which is immune‐privileged, and in the tumor. However, CTAs are self‐antigens and natural TCRs to CTAs have low affinity/avidity due to central tolerance. We previously described a method of directed evolution of TCR avidity using somatic hypermutation. In this study, we made several improvements to this method and enhanced the avidity of the hT27 TCR, which is specific for the cancer testis antigen HLA‐A2‐MAGE‐A1278‐286. We identified eight point mutations with varying degrees of improved avidity. Human T cells transduced with TCRs containing these mutations displayed enhanced tetramer binding, IFN‐γ and IL2 production, and cytotoxicity. Most of the mutations have retained specificity, except for one mutant with extremely high avidity. We demonstrate that somatic hypermutation is capable of optimizing avidity of clinically relevant TCRs for immunotherapy. [ABSTRACT FROM AUTHOR]

Single-cell TCR repertoire analysis reveals highly polyclonal composition of human intraepithelial CD8+ T lymphocytes in untreated celiac disease Keywords: CD8+ T cells; celiac disease; intraepithelial lymphocytes; single cell sequencing; TCR EN CD8+ T cells celiac disease intraepithelial lymphocytes single cell sequencing TCR 1542 1545 4 06/09/21 20210601 NES 210601 We compared the T-cell receptor repertoires of CD8 SP + sp intraepithelial lymphocytes from celiac disease patients and healthy subjects by single-cell sequencing. GLO:BVO/01jun21:eji4997-gra-0001.jpg PHOTO (COLOR): . gl Abbreviations CeD celiac disease UCeD untreated CeD TCeD treated CeD GFD gluten-free diet IEL intraepithelial lymphocyte Celiac disease (CeD) is a chronic inflammatory disease driven by exposure to dietary gluten. [Extracted from the article]

Summary: Within each individual, the adaptive immune system generates a repertoire of cells expressing receptors capable of recognizing diverse potential pathogens. The theoretical diversity of the T‐cell receptor (TCR) repertoire exceeds the actual size of the T‐cell population in an individual by several orders of magnitude – making the observation of identical TCRs in different individuals extremely improbable if all receptors were equally likely. Despite this disparity between the theoretical and the realized diversity of the repertoire, these 'public' receptor sequences have been identified in autoimmune, cancer and pathogen interaction contexts. Biased generation processes explain the presence of public TCRs in the naive repertoire, but do not adequately explain the different abundances of these public TCRs. We investigate and characterize the distribution of genomic TCR‐β sequences of naive CD8+ T cells from three genetically identical mice, comparing non‐productive (non‐functional sequences) and productive sequences. We find public TCR‐β sequences at higher abundances compared with unshared sequences in the productive, but not in the non‐productive, repertoire. We show that neutral processes such as recombination biases, codon degeneracy and generation probability do not fully account for these differences, and conclude that thymic or peripheral selection plays an important role in increasing the abundances of public TCR‐β sequences. [ABSTRACT FROM AUTHOR]

Keywords: celiac; gluten; HLA-DQ2.5; mouse; TCR EN celiac gluten HLA-DQ2.5 mouse TCR 1002 1005 4 04/19/21 20210401 NES 210401 We created a TCR transgenic mouse with CD4 SP + sp T cells recognizing the immunodominant DQ2.5-glia- 2 gluten epitope. We have recently created transgenic (tg) mice expressing celiac patient-derived T-cell receptors (TCRs) recognizing the DQ2.5-glia- 2 gluten epitope [3] and here report the generation of a TCR tg mouse specific for the DQ2.5-glia- 2 epitope. Characterization of T-cell receptor transgenic mice recognizing immunodominant HLA-DQ2.5-restricted gluten epitopes. [Extracted from the article]

It has been appreciated for more than three decades that the interactions between the T‐cell antigen receptor and self‐antigens are the major determinants of the cell fates of developing thymocytes and the establishment of central tolerance. However, recent evidence shows that the level of self‐reactivity substantially contributes to fate choices of positively selected mature T cells in homeostasis, as well as during immune responses. This implies that individual clones of peripheral T cells are predisposed to specific functional properties based on the self‐reactivity of their antigen receptors. Overall, the relative difference in the self‐reactivity among peripheral T cells is an important factor contributing to the diversity of T‐cell responses to foreign antigens. [ABSTRACT FROM AUTHOR]

Diacylglycerol kinases (DGKs) play important roles in restraining diacylglycerol (DAG)‐mediated signaling. Within the DGK family, the ζ isoform appears to be the most important isoform in T cells for controlling their development and function. DGKζ has been demonstrated to regulate T cell maturation, activation, anergy, effector/memory differentiation, defense against microbial infection, and antitumor immunity. Given its critical functions, DGKζ function should be tightly regulated to ensure proper signal transduction; however, mechanisms that control DGKζ function are still poorly understood. We report here that DGKζ dynamically translocates from the cytosol into the nuclei in T cells after TCR stimulation. In mice, DGKζ mutant defective in nuclear localization displayed enhanced ability to inhibit TCR‐induced DAG‐mediated signaling in primary T cells, maturation of conventional αβT and iNKT cells, and activation of peripheral T cells compared with WT DGKζ. Our study reveals for the first time nuclear sequestration of DGKζ as a negative control mechanism to spatially restrain it from terminating DAG mediated signaling in T cells. Our data suggest that manipulation of DGKζ nucleus‐cytosol shuttling as a novel strategy to modulate DGKζ activity and immune responses for treatment of autoimmune diseases and cancer. [ABSTRACT FROM AUTHOR]

Malignant melanoma has seen monumental changes in treatment options the last decade from the very poor results of dacarbazine treatment to the modern‐day use of targeted therapies and immune checkpoint inhibitors. Melanoma has a high mutational burden making it more capable of evoking immune responses than many other tumours. Even when considering double immune checkpoint blockade with anti‐CTLA‐4 and anti‐PD‐1, we still have far to go in melanoma treatment as 50% of patients with metastatic disease do not respond to current treatment. Alternative immunotherapy should therefore be considered. Since melanoma has a high mutational burden, it is considered more immunogenic than many other tumours. T cell receptor (TCR) therapy could be a possible way forward, either alone or in combination, to improve the response rates of this deadly disease. Melanoma is one of the cancers where TCR therapy has been frequently applied. However, the number of antigens targeted remains fairly limited, although advanced personalized therapies aim at also targeting private mutations. In this review, we look at possible aspects of targeting TCR therapy towards melanoma and provide an implication of its use in the future. [ABSTRACT FROM AUTHOR]

Invariant Natural Killer T (iNKT) cells are particular T lymphocytes at the frontier between innate and adaptative immunities. They participate in the elimination of pathogens or tumor cells, but also in the development of allergic reactions and autoimmune diseases. From their first descriptions, the phenomenon of self‐reactivity has been described. Indeed, they are able to recognize exogenous and endogenous lipids. However, the mechanisms underlying the self‐reactivity are still largely unknown, particularly in humans. Using a CD1d tetramer‐based sensitive immunomagnetic approach, we generated self‐reactive iNKT cell lines from blood circulating iNKT cells of healthy donors. Analysis of their functional characteristics in vitro showed that these cells recognized endogenous lipids presented by CD1d molecules through their TCR that do not correspond to α‐glycosylceramides. TCR sequencing and transcriptomic analysis of T cell clones revealed that a particular TCR signature and an expression of the SYK protein kinase were two mechanisms supporting human iNKT self‐reactivity. The SYK expression, strong in the most self‐reactive iNKT clones and variable in ex vivo isolated iNKT cells, seems to decrease the activation threshold of iNKT cells and increase their overall antigenic sensitivity. This study indicates that a modulation of the TCR intracellular signal contributes to iNKT self‐reactivity. [ABSTRACT FROM AUTHOR]

Adoptive T cell therapy using tumor‐specific T cells or TCR‐modified T cells is a promising next‐generation immunotherapy. The major source of tumor‐reactive T cells is PD‐1+ tumor‐infiltrating lymphocytes (TILs). In contrast, PD‐1− TILs have received little attention. Here, we analyzed the TCR‐β repertoires of PD‐1− and PD‐1+ CD8+ TILs derived from colorectal cancer and breast cancer. Approximately 40–60% of the PD‐1+ population consisted of oligoclonal populations in both colorectal cancer and breast cancer. In contrast, approximately 37% of the PD‐1− population consisted of an oligoclonal population in colorectal cancer, whereas 14% of them were oligoclonal in breast cancer. In colorectal cancer, the TCR repertoires of PD‐1−CD8+ TILs and PD‐1+CD8+ TILs hardly overlapped. Interestingly, clonally expanded CD8+ TILs in primary tumors and the metastases expressing the same clonotypic TCR showed the same phenotype regarding the PD‐1‐expression. These results suggest that the intrinsic properties of TCRs determine the fate of TILs in terms of whether they become PD‐1+ or PD‐1− in the tumor microenvironment. Further functional analysis of TCRs in TILs will allow us to better understand the regulatory mechanisms for PD‐1 expression on TILs and may contribute to tumor immunotherapy. [ABSTRACT FROM AUTHOR]

Strategies employed by pathogenic enteric bacteria, such as Shigella, to subvert the host adaptive immunity are not well defined. Impairment of T lymphocyte chemotaxis by blockage of polarised edge formation has been reported upon Shigella infection. However, the functional impact of Shigella on T lymphocytes remains to be determined. Here, we show that Shigella modulates CD4+ T cell F‐actin dynamics and increases cell cortical stiffness. The scanning ability of T lymphocytes when encountering antigen‐presenting cells (APC) is subsequently impaired resulting in decreased cell–cell contacts (or conjugates) between the two cell types, as compared with non‐infected T cells. In addition, the few conjugates established between the invaded T cells and APCs display no polarised delivery and accumulation of the T cell receptor to the contact zone characterising canonical immunological synapses. This is most likely due to the targeting of intracellular vesicular trafficking by the bacterial type III secretion system (T3SS) effectors IpaJ and VirA. The collective impact of these cellular reshapings by Shigella eventually results in T cell activation dampening. Altogether, these results highlight the combined action of T3SS effectors leading to T cell defects upon Shigella infection. [ABSTRACT FROM AUTHOR]

The development of self antigen‐specific T cells is influenced by how the self antigen is expressed. Here, we created a mouse in which a model self antigen is conditionally expressed in different tissue environments. Using peptide:MHCII tetramer‐based cell enrichment methods, we examined the development of corresponding endogenous self antigen‐specific CD4+ T cell populations. While ubiquitous self antigen expression resulted in efficient deletion of self antigen‐specific T cells in the thymus, some tissue‐restricted expression patterns resulted in partial deletion of the population in peripheral lymphoid organs. Deletion specifically affected Foxp3− conventional T cells (Tconv) with a bias towards high avidity TCR expressing cells in the case of thymic, but not peripheral deletion. In contrast, Foxp3+ Treg exhibited elevated frequencies with increased TCR avidity. T cells surviving deletion were functionally impaired, with Tconv cells exhibiting more impairment than Tregs. Collectively, our results illustrate how postthymic recognition of tissue‐restricted self antigens results in opposing developmental fates for Tconv and Treg cell subsets. [ABSTRACT FROM AUTHOR]

A TRAV26-1-encoded recognition motif focuses the biased T cell response in celiac disease Both TCR 364 and TCR S16 are prototypic DQ2.5-glia- 2-specific TCRs, but use different I TRAJ i gene segments ( I TRAJ43*01 i and I TRAJ32*01 i ) and thus differ in their CDR3 loops which may affect how they react to pMHC (Fig. Co-crystal structure of TCR S16 (grey) with HLA-DQ2.5:DQ2.5-glia- 2 (MHC -chain: green). A model of TCR AV5 bound to pMHC was generated using the TCRmodel webserver, superimposed with TCR S16, minimized into the Rosetta score function, and compared to the co-crystal structure of TCR S16 (E). [Extracted from the article]

The rabbit has been widely used in immunology and infectiology. Rabbit immunoglobulins have been extensively studied, leading to the discovery of their idiotypes, allotypic diversity, and of the diversification of the primary repertoire by hyperconversion. Much less is known about rabbit T cell receptors (TR), especially TRA. This isotype is particularly important for innate‐like T cells, which typically express invariant TRA (iTRA). The presence of such cells in the rabbit remains an enigma. Rabbit NKT cells seem to be very rare, and lagomorphs lack MAIT cells. TRAV1, the variable gene expressed in the iTRA of these cells across most mammals, and MR1, the MH1‐like receptor that present riboflavin derivatives to MAIT cells, are missing in rabbit. An alternative iTRA has been identified, that may be expressed by new innate‐like T cells. To facilitate TRA repertoire analyses in rabbit, we report here a full description of TRA and TRD loci and a subgroup definition based on IMGT® classification. Rabbit TRA rearrangements follow the same temporal pattern that is observed in mouse and human. Rare transcripts expressing TRDV/TRDD/TRDJ rearrangements spliced to TRAC were detected. TRA and TRD genes have been made available in IMGT and IMGT/HighV‐QUEST, allowing easy analysis of TRA/TRD RepSeq. [ABSTRACT FROM AUTHOR]

Adoptive transfer of T cells that have been genetically modified to express an antitumor T‐cell receptor (TCR) is a potent immunotherapy, but only if TCR avidity is sufficiently high. Endogenous TCRs specific to shared (self) tumor‐associated antigens (TAAs) have low affinity due to central tolerance. Therefore, for effective therapy, anti‐TAA TCRs with higher and optimal avidity must be generated. Here, we describe a new in vitro system for directed evolution of TCR avidity using somatic hypermutation (SHM), a mechanism used in nature by B cells for antibody optimization. We identified 44 point mutations to the Pmel‐1 TCR, specific for the H‐2Db‐gp10025‐33 melanoma antigen. Primary T cells transduced with TCRs containing two or three of these mutations had enhanced activity in vitro. Furthermore, the triple‐mutant TCR improved in vivo therapy of tumor‐bearing mice, which exhibited improved survival, smaller tumors and delayed or no relapse. TCR avidity maturation by SHM may be an effective strategy to improve cancer immunotherapy. What's new? Immunotherapies such as CAR‐T and adoptive T cell therapy use T cells that recognize and attack specific antigens on cancer cells. However, many of these antigens occur on both cancer and normal cells, and the T‐cell receptors (TCRs) don't bind very well. In this study, the authors used a technique called somatic hypermutation (SHM) to improve TCR binding. They then tested this approach in tumor‐bearing mice, and found that T cells carrying a mutated TCR improved survival and reduced tumor size. SHM may thus help to improve TCR binding for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

T‐lymphocyte activation relies on the cognate recognition by the TCR of the MHC‐associated peptide ligand (pMHC) presented at the surface of an antigen‐presenting cell (APC). This leads to the dynamic formation of a cognate contact between the T lymphocyte and the APC: the immune synapse (IS). Engagement of the TCR by the pMHC in the synaptic zone induces a cascade of signaling events leading to phosphorylation and dephosphorylation of proteins and lipids, which ultimately shapes the response of T lymphocytes. Although the engagement of the T‐cell receptor (TCR) takes place at the plasma membrane, the TCR/CD3 complexes and the signaling molecules involved in transduction of the TCR signal are also present in intracellular membrane pools. These pools, which are both endocytic and exocytic, have tentatively been characterized by several groups including ours. We will herein summarize what is known on the intracellular pools of TCR signaling components. We will discuss their origin and the mechanisms involved in their mobility at the IS. Finally, we will propose several hypotheses concerning the functional role(s) that these intracellular pools might play in T‐cell activation. We will also discuss the tools that could be used to test these hypotheses. [ABSTRACT FROM AUTHOR]

The αβ T‐cell receptor (TCR) is a multiprotein complex controlling the activation of T cells. Although the structure of the complete TCR is not known, cumulative evidence supports that the TCR cycles between different conformational states that are promoted either by thermal motion or by force. These structural transitions determine whether the TCR engages intracellular effectors or not, regulating TCR phosphorylation and signaling. As for other membrane receptors, ligand binding selects and stabilizes the TCR in active conformations, and/or switches the TCR to activating states that were not visited before ligand engagement. Here we review the main models of TCR allostery, that is, ligand binding at TCRαβ changes the structure at CD3 and ζ. (a) The ITAM and proline‐rich sequence exposure model, in which the TCR's cytoplasmic tails shield each other and ligand binding exposes them for phosphorylation. (b) The membrane‐ITAM model, in which the CD3ε and ζ tails are sequestered inside the membrane and again ligand binding exposes them. (c) The mechanosensor model in which ligand binding exerts force on the TCR, inducing structural changes that allow signaling. Since these models are complementary rather than competing, we propose a unified model that aims to incorporate all existing data. [ABSTRACT FROM AUTHOR]

The peripheral maturation of human CD1d‐restricted natural killer T (NKT) cells has not been well described. In this study, we identified four major subsets of NKT cells in adults, distinguished by the expression of CD4, CD8 and CCR5. Phenotypic analysis suggested a hierarchical pattern of differentiation, whereby immature CD4+CD8−CCR5− cells progressed to an intermediate CD4+CD8−CCR5+ stage, which remained less differentiated than the CD4−CD8− and CD4−CD8+ subsets, both of which expressed CCR5. This interpretation was supported by functional data, including clonogenic potential and cytokine secretion profiles, as well as T‐cell receptor (TCR) excision circle analysis. Moreover, conventional and high‐throughput sequencing of the corresponding TCR repertoires demonstrated significant clonotypic overlap within individuals, especially between the more differentiated CD4−CD8− and CD4−CD8+ subsets. Collectively, these results mapped a linear differentiation pathway across the post‐thymic landscape of human CD1d‐restricted NKT cells. [ABSTRACT FROM AUTHOR]

It is established that iNKT cells are a cell type that require strong TCR signal for their proper development and represent a model for thymic agonist selection. The nature of the signal perceived by iNKT cells promoting their specification is not well understood. To address this question, we analyzed iNKT cell development in relevant TCR Vα14‐Jα18 alpha chain transgenic mice (Vα14Tg). In CD4‐Vα14Tg mice, where the transgene is driven by CD4 promoter, we identified a block in iNKT cell development at early developmental stages due to a reduced expression of key transcription factors accompanied with a reduced TCR expression levels. This indicates that TCR signal strength control iNKT cell differentiation. Importantly, we found in WT mice that early precursors of iNKT cells express higher TCR levels compared to positively selected precursors of mainstream T cells showing that TCR levels could contribute to the strength of iNKT cell TCR signaling. Overall, our study highlights TCR signal strength associated with a higher TCR density as an important regulator of iNKT cell lineage specification. [ABSTRACT FROM AUTHOR]

The transcription factor Helios is expressed in a large subset of Foxp3+ Tregs. We previously proposed that Helios is a marker of thymic derived Treg (tTreg), while Helios− Treg were induced from Foxp3− T conventional (Tconv) cells in the periphery (pTreg). To compare the two Treg subpopulations, we generated Helios‐GFP reporter mice and crossed them to Foxp3‐RFP reporter mice. The Helios+ Treg population expressed a more activated phenotype, had a slightly higher suppressive capacity in vitro and expressed a more highly demethylated TSDR but were equivalent in their ability to suppress inflammatory bowel disease in vivo. However, Helios+ Treg more effectively inhibited the proliferation of activated, autoreactive splenocytes from scurfy mice. When Helios+ and Helios− Treg were transferred to lymphoreplete mice, both populations maintained comparable Foxp3 expression, but Foxp3 expression was less stable in Helios− Treg when transferred to lymphopenic mice. Gene expression profiling demonstrated a large number of differentially expressed genes and showed that Helios− Treg expressed certain genes normally expressed in CD4+Foxp3− T cells. TCR repertoire analysis indicated very little overlap between Helios+ and Helios− Treg. Thus, Helios+ and Helios− Treg subpopulations are phenotypically and functionally distinct and express dissimilar TCR repertoires. Helios− and Helios+ Treg represent two distinct populations and express dissimilar TCR repertoires. Foxp3 expression is stable in Helios+ Treg and they effectively suppress autoimmunity. Foxp3 is less stable in Helios− Treg, some convert to effector cells, and they suppress some (IBD), but not all autoreactive (Scurfy) responses in vivo. [ABSTRACT FROM AUTHOR]

Thymus‐derived regulatory T cells (tTregs) play pivotal roles in immunological self‐tolerance and homeostasis. A majority of tTregs are reactive to self‐antigens and are constantly exposed to antigenic stimulation. Despite this continuous stimulation, tTreg and conventional T‐cell populations remain balanced during homeostasis, but the mechanisms controlling this balance are unknown. We previously reported a form of activation‐induced cell death, which is dependent on p53 (p53‐induced CD28‐dependent T‐cell apoptosis, PICA). Under PICA‐inducing conditions, tTregs survive while a majority of conventional T cells undergo apoptosis, suggesting there is a survival mechanism that protects tTregs. Here, we report that the expression of RasGRP1 (Ras guanyl‐releasing protein 1) is required for PICA, as conventional T cells isolated from RasGRP1‐deficient mice become resistant to PICA. After continuous stimulation, tTregs express a substantially lower amount of RasGRP1 compared to conventional T cells. This reduced expression of RasGRP1 is dependent on TGF‐β, as addition of TGF‐β to conventional T cells reduces RasGRP1 expression. Conversely, RasGRP1 expression in tTregs increases when TGF‐β signaling is inhibited. Together, these data show that RasGRP1 expression is repressed in tTregs by TGF‐β signaling and suggests that reduced RasGRP1 expression is critical for tTregs to resist apoptosis caused by continuous antigen exposure. Tregs exhibit reduced RasGRP1 expression compared to conventional T cells in response to continuous stimulation. Furthermore, RasGRP1 expression is repressed in Tregs by TGF‐β signaling. We propose a model where reduced RasGRP1 expression is critical for Tregs to resist apoptosis caused by continuous antigen exposure. [ABSTRACT FROM AUTHOR]

Abstract: The peptide (P) ligand seen by the TCR is presented by an MHC‐encoded restricting element (R). Peptide is viewed from two perspectives, that of the TCR and that of R. The TCR looks at P using an anti‐P site that is somatically generated and selected, whereas R looks at P using a binding site that is germline generated and selected. The two segments of P, the one viewed by the TCR, the other viewed by R divide P into two repertoires, Ptcr and Pr that are recognized independently but function cooperatively. The consequences of this for an understanding of TCR specificity and signalling as well as the role of differential processing are analysed. It is ironic that from the point of view of the immunologist, the TCR is highly polyreactive recognizing over a million peptides, whereas from the point of view of the immune system, the TCR is highly specific recognizing essentially only one epitope. [ABSTRACT FROM AUTHOR]

Abstract: Mucosa‐associated lymphoid tissue 1 (Malt1) regulates immune cell function by mediating the activation of nuclear factor κB (NF‐κB) signaling through both its adaptor and proteolytic function. Malt1 is also a target of its own protease activity and this self‐cleavage further contributes to NF‐κB activity. Until now, the functional distinction between Malt1 self‐cleavage and its general protease function in regulating NF‐κB signaling and immune activation remained unclear. Here we demonstrate, using a new mouse model, the importance of Malt1 self‐cleavage in regulating expression of NF‐κB target genes and subsequent T cell activation. Significantly, we further establish that Treg homeostasis is critically linked to Malt1 function via a Treg intrinsic and extrinsic mechanism. TCR‐mediated Malt1 proteolytic activity and self‐cleavage was found to drive Il2 expression in conventional CD4+ T cells, thereby regulating Il2 availability for Treg homeostasis. Remarkably, the loss of Malt1‐mediated self‐cleavage alone was sufficient to cause a significant Treg deficit resulting in increased anti‐tumor immune reactivity without associated autoimmunity complications. These results establish for the first time that inhibition of MALT1 proteolytic activity could be a viable therapeutic strategy to augment anti‐tumor immunity. [ABSTRACT FROM AUTHOR]