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CD8 + T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tT ex ) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8 + tT ex cells possess transcriptional features of CD4 + Foxp3 + regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tT ex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8 + T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tT ex cells by tumor hypoxia, thus mitigation of hypoxia limits tT ex suppression. Together, these data suggest tT ex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy. Exhausted CD8 + T cells with diminished effector functions accumulate in tumors. Here, the authors show that hypoxia induces a suppressive phenotype in exhausted T cells and that interfering with hypoxia-mediated CD39 expression limits immunosuppression in the tumor and augments immunotherapy, resulting in arrest of tumor growth.

Follicular helper T (TFH) cells provide help to B cells, supporting the formation of germinal centres that allow affinity maturation of antibody responses. Although usually located in secondary lymphoid organs, T cells bearing features of TFH cells can also be identified in human blood, and their frequency and phenotype are often altered in people with autoimmune diseases. In this Perspective article, I discuss the increase in circulating TFH cells seen in autoimmune settings and explore potential explanations for this phenomenon. I consider the multistep regulation of TFH cell differentiation by the CTLA4 and IL-2 pathways as well as by regulatory T cells and highlight that these same pathways are crucial for regulating autoimmune diseases. The propensity of infection to serve as a cue for TFH cell differentiation and a potential trigger for autoimmune disease development is also discussed. Overall, I postulate that alterations in pathways that regulate autoimmunity are coupled to alterations in TFH cell homeostasis, suggesting that this population may serve as a core sentinel of dysregulated immunity.Individuals with autoimmunity often have an increased frequency of T cells bearing features of follicular helper T cells in their blood. Lucy Walker proposes that alterations in pathways that regulate autoimmunity are coupled to alterations in follicular helper T cell homeostasis.

Cancer and chronic infections induce T cell exhaustion, a hypofunctional fate carrying distinct epigenetic, transcriptomic and metabolic characteristics. However, drivers of exhaustion remain poorly understood. As intratumoral exhausted T cells experience severe hypoxia, we hypothesized that metabolic stress alters their responses to other signals, specifically, persistent antigenic stimulation. In vitro, although CD8 + T cells experiencing continuous stimulation or hypoxia alone differentiated into functional effectors, the combination rapidly drove T cell dysfunction consistent with exhaustion. Continuous stimulation promoted Blimp-1-mediated repression of PGC-1α-dependent mitochondrial reprogramming, rendering cells poorly responsive to hypoxia. Loss of mitochondrial function generated intolerable levels of reactive oxygen species (ROS), sufficient to promote exhausted-like states, in part through phosphatase inhibition and the consequent activity of nuclear factor of activated T cells. Reducing T cell–intrinsic ROS and lowering tumor hypoxia limited T cell exhaustion, synergizing with immunotherapy. Thus, immunologic and metabolic signaling are intrinsically linked: through mitigation of metabolic stress, T cell differentiation can be altered to promote more functional cellular fates. Delgoffe and colleagues show that continuous TCR signaling and hypoxia increase Blimp-1, which suppresses PGC-1α-dependent mitochondrial reprogramming and increases reactive oxygen species generation. Such conditions promote T cell exhaustion.

Following their exit from the thymus, T cells are endowed with potent effector functions but must spare host tissue from harm. The fate of these cells is dictated by a series of checkpoints that regulate the quality and magnitude of T cell-mediated immunity, known as tolerance checkpoints. In this Perspective, we discuss the mediators and networks that control the six main peripheral tolerance checkpoints throughout the life of a T cell: quiescence, ignorance, anergy, exhaustion, senescence and death. At the naive T cell stage, two intrinsic checkpoints that actively maintain tolerance are quiescence and ignorance. In the presence of co-stimulation-deficient T cell activation, anergy is a dominant hallmark that mandates T cell unresponsiveness. When T cells are successfully stimulated and reach the effector stage, exhaustion and senescence can limit excessive inflammation and prevent immunopathology. At every stage of the T cell’s journey, cell death exists as a checkpoint to limit clonal expansion and to terminate unrestrained responses. Here, we compare and contrast the T cell tolerance checkpoints and discuss their specific roles, with the aim of providing an integrated view of T cell peripheral tolerance and fate regulation.A number of T cell-intrinsic peripheral tolerance mechanisms (quiescence, ignorance, anergy, exhaustion, senescence and cell death) restrain autoimmunity and overactive immune responses. Here, the authors provide an integrated perspective of peripheral T cell tolerance by comparing the molecular mechanisms that govern these checkpoints and discussing their role in T cell tolerance and fate regulation.

Key Points Regulatory T (T Reg ) cells are a distinct lineage of CD4 + T cells that differentiate in response to agonist self antigens in the thymus and to non-pathogenic foreign antigens in the periphery. The involvement of T cell receptor (TCR) signalling modules that have opposing activities in T cell lineage specification favours a T Reg cell repertoire that, in general, reacts to low-abundance, high-affinity antigens. Compared with ubiquitous antigens, low-abundance, high-affinity antigens will probably induce inefficient clonal deletion of T cells, and thus the existence of these antigens justifies the necessity of T Reg cell-mediated dominant immune tolerance. Depending on the expression of activation markers, mature T Reg cells can be divided into resting and activated T Reg cell subsets, and these discrete populations probably accompany conventional T cells to control their activation and effector functions in secondary lymphoid organs and target tissues. Distinct TCR signalling modules are selectively involved in the control of trafficking, maintenance and suppressive activities of resting and activated T Reg cells. In this Review, the authors discuss the emerging role of T cell receptor (TCR) specificity and signalling in the differentiation, maintenance and function of regulatory T (T Reg ) cells. Understanding how TCR signalling regulates T Reg cells has important therapeutic implications in the regulation of immune tolerance and inflammation. Regulatory T cells (T Reg cells), a specialized T cell lineage, have a pivotal function in the control of self tolerance and inflammatory responses. Recent studies have revealed a discrete mode of T cell receptor (TCR) signalling that regulates T Reg cell differentiation, maintenance and function and that affects gene expression, metabolism, cell adhesion and migration of these cells. Here, we discuss the emerging understanding of TCR-guided differentiation of T Reg cells in the context of their function in health and disease.

Impaired chronic viral and tumor clearance has been attributed to CD8+ T cell exhaustion, a differentiation state in which T cells have reduced and altered effector function that can be partially reversed upon blockade of inhibitory receptors. The role of the exhaustion program and transcriptional networks that control CD8+ T cell function and fate in autoimmunity is not clear. Here we show that intra-islet CD8+ T cells phenotypically, transcriptionally, epigenetically and metabolically possess features of canonically exhausted T cells, yet maintain important differences. This ‘restrained’ phenotype can be perturbed and disease accelerated by CD8+ T cell-restricted deletion of the inhibitory receptor lymphocyte activating gene 3 (LAG3). Mechanistically, LAG3-deficient CD8+ T cells have enhanced effector-like functions, trafficking to the islets, and have a diminished exhausted phenotype, highlighting a physiological role for an exhaustion program in limiting autoimmunity and implicating LAG3 as a target for autoimmune therapy.Exhausted T cells are associated with inefficient viral clearance, tumor immunity and response to immunotherapy. Here the authors show CD8+ T cells in the pancreatic islets have a LAG3-promoted ‘restrained’ phenotype resembling exhausted cells but maintain effector functions, and LAG3 expression limits pathology in the nonobese diabetic mouse model of type 1 diabetes.

Immune cells at sites of inflammation are continuously activated by local antigens and cytokines, and regulatory mechanisms must be enacted to control inflammation. The stepwise hydrolysis of extracellular ATP by ectonucleotidases CD39 and CD73 generates adenosine, a potent immune suppressor. Here we report that human effector CD8 T cells contribute to adenosine production by releasing CD73-containing extracellular vesicles upon activation. These extracellular vesicles have AMPase activity, and the resulting adenosine mediates immune suppression independently of regulatory T cells. In addition, we show that extracellular vesicles isolated from the synovial fluid of patients with juvenile idiopathic arthritis contribute to T cell suppression in a CD73-dependent manner. Our results suggest that the generation of adenosine upon T cell activation is an intrinsic mechanism of human effector T cells that complements regulatory T cell-mediated suppression in the inflamed tissue. Finally, our data underscore the role of immune cell-derived extracellular vesicles in the control of immune responses. Ectonucleotidases associated to regulatory T cells are known modulators in the inflammatory environment. Here the authors describe CD8 T cell-derived extracellular vesicles bearing CD73 and suggest they function as an additional intrinsic modulator of immune responses.

Forkhead box protein 3-expressing (FOXP3+) regulatory T cells (Treg cells) suppress conventional T cells and are essential for immunological tolerance. FOXP3, the master transcription factor of Treg cells, controls the expression of multiples genes to guide Treg cell differentiation and function. However, only a small fraction (<10%) of Treg cell-associated genes are directly bound by FOXP3, and FOXP3 alone is insufficient to fully specify the Treg cell programme, indicating a role for other accessory transcription factors operating upstream, downstream and/or concurrently with FOXP3 to direct Treg cell specification and specialized functions. Indeed, the heterogeneity of Treg cells can be at least partially attributed to differential expression of transcription factors that fine-tune their trafficking, survival and functional properties, some of which are niche-specific. In this Review, we discuss the emerging roles of accessory transcription factors in controlling Treg cell identity. We specifically focus on members of the basic helix–loop–helix family (AHR), basic leucine zipper family (BACH2, NFIL3 and BATF), CUT homeobox family (SATB1), zinc-finger domain family (BLIMP1, Ikaros and BCL-11B) and interferon regulatory factor family (IRF4), as well as lineage-defining transcription factors (T-bet, GATA3, RORγt and BCL-6). Understanding the imprinting of Treg cell identity and specialized function will be key to unravelling basic mechanisms of autoimmunity and identifying novel targets for drug development.Regulatory T cells (Treg cells) are controlled by a raft of transcription factors besides Forkhead box protein 3 (FOXP3). As detailed in this Review, these accessory transcription factors act alone or together with FOXP3 to coordinate Treg cell specification and function, and account for heterogeneity of niche-specific Treg cells.

Regulatory T (T reg ) cells derived from the thymus (tT reg ) and periphery (pT reg ) have central and distinct functions in immunosuppression, but mechanisms for the generation and activation of T reg subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tT reg and pT reg cells. mTOR signaling is crucial for programming activated T reg -cell function to protect immune tolerance and tissue homeostasis. T reg -specific deletion of mTOR drives spontaneous effector T-cell activation and inflammation in barrier tissues and is associated with reduction in both thymic-derived effector T reg (eT reg ) and pT reg cells. Mechanistically, mTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, deletion of mitochondrial transcription factor A (Tfam) severely impairs T reg -cell suppressive function and eT reg -cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated T reg subsets to mediate tissue homeostasis. The authors previously showed that mTOR controls the function of regulatory T cells. Here they show how this mTOR signaling orchestrates homeostasis of T reg -cell subsets and prevents fatal autoimmunity.

Whole-body metabolism can affect immune-cell function and vice versa. Turka and colleagues review the unique metabolic properties of T reg cells and how this relates to their function and the outcome of immune responses. The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells.