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The transcription factor Foxp3 is essential for the function of regulatory T cells. Rudensky and colleagues show Foxp3 participates in large protein complexes that regulate gene expression of many of these components in self-reinforcing networks. The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (T reg cells). To gain insights into the molecular mechanisms of Foxp3-mediated gene expression, we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multiprotein complexes of 400–800 kDa or larger and identified 361 associated proteins, ∼30% of which were transcription related. Foxp3 directly regulated expression of a large proportion of the genes encoding its cofactors. Some transcription factor partners of Foxp3 facilitated its expression. Functional analysis of the cooperation of Foxp3 with one such partner, GATA-3, provided additional evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of T reg cell biology.

Regulatory T cells expressing the transcription factor T-bet selectively suppress T H 1 and CD8 T cells, but not T H 2 or T H 17 activation and associated autoimmunity. Adaptive immune responses are tailored to different types of pathogens through differentiation of naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (T H 1), T H 2, and T H 17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively 1 . Regulatory T (T reg ) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2 , 3 ). Paradoxically, some activated T reg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide T reg cells with enhanced suppressive capacity 4 , 5 , 6 . Whether expression of these factors in T reg cells—as in effector T cells—is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here we demonstrate that expression of the T H 1-associated transcription factor T-bet in mouse T reg cells, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss of function or elimination of T-bet-expressing T reg cells—but not of T-bet expression in T reg cells—resulted in severe T H 1 autoimmunity. Conversely, following depletion of T-bet − T reg cells, the remaining T-bet + cells specifically inhibited T H 1 and CD8 T cell activation consistent with their co-localization with T-bet + effector T cells. These results suggest that T-bet + T reg cells have an essential immunosuppressive function and indicate that T reg cell functional heterogeneity is a critical feature of immunological tolerance.

Tissue maintenance and homeostasis can be achieved through the replacement of dying cells by differentiating precursors or self-renewal of terminally differentiated cells or relies heavily on cellular longevity in poorly regenerating tissues. Regulatory T cells (T reg cells) represent an actively dividing cell population with critical function in suppression of lethal immune-mediated inflammation. The plasticity of T reg cells has been actively debated because it could factor importantly in protective immunity or autoimmunity. By using inducible labeling and tracking of T reg cell fate in vivo, or transfers of highly purified T reg cells, we have demonstrated notable stability of this cell population under physiologic and inflammatory conditions. Our results suggest that self-renewal of mature T reg cells serves as a major mechanism of maintenance of the T reg cell lineage in adult mice.

In this Viewpoint article, several experts share their thoughts on the plasticity and stability of regulatory T cells, discussing the recent advances in our understanding of the transcriptional and epigenetic regulation of this important T cell subset, as well as the therapeutic implications of this research. Regulatory T (T Reg ) cells are crucial for the prevention of fatal autoimmunity in mice and humans. Forkhead box P3 (FOXP3) + T Reg cells are produced in the thymus and are also generated from conventional CD4 + T cells in peripheral sites. It has been suggested that FOXP3 + T Reg cells might become unstable under certain inflammatory conditions and might adopt a phenotype that is more characteristic of effector CD4 + T cells. These suggestions have caused considerable debate in the field and have important implications for the therapeutic use of T Reg cells. In this article, Nature Reviews Immunology asks several experts for their views on the plasticity and stability of T Reg cells.

Complete T cell development requires postthymic maturation, and we investigated the influence of this ontological period on the CD8 T cell response to infection by comparing responses of mature CD8 T cells with those of recent thymic emigrants (RTEs). When activated with a noninflammatory stimulus or a bacterial or viral pathogen, CD8 RTEs generated a lower proportion of cytokine-producing effector cells and long-lived memory precursors compared with their mature counterparts. Although peripheral T cell maturation is complete within several weeks after thymic egress, RTE-derived memory cells continued to express inappropriate levels of memory cell markers and display an altered pattern of cytokine production, even 8 weeks after infection. When rechallenged, RTE-derived memory cells generated secondary effector cells that were phenotypically and functionally equivalent to those generated by their mature counterparts. The defects at the effector and memory stages were not associated with differences in the expression of T cell receptor-, costimulation-, or activation-associated cell surface markers yet were associated with lower Ly6C expression levels at the effector stage. This work demonstrates that the stage of postthymic maturation influences cell fate decisions and cytokine profiles of stimulated CD8 T cells, with repercussions that are apparent long after cells have progressed from the RTE compartment.

Treatment of HER2-positive metastatic breast cancer with ado-trastuzumab emtansine (T-DM1), a novel antibody–drug conjugate, has resulted in both improved progression-free and overall survival. Recognition and treatment of diverse adverse events related to T-DM1 is critical for safety and tolerability. The most frequent adverse events with T-DM1 include fatigue, diarrhea, anemia, elevated transaminases, and mild-to-moderate hemorrhagic events, which are thought to be related to induced thrombocytopenia. Here, we present five case series of cutaneous and mucosal telangiectasias, definitely related to T-DM1. The development of telangiectasias represents a newly recognized adverse effect of T-DM1. We provide description and timing of the telangiectasias and review the mechanisms that may explain the formation of these vascular lesions in association with T-DM1. Further, we describe associated bleeding events and propose that induced telangiectasias could represent an additional cause of T-DM1-associated hemorrhage.

This corrects the article DOI: 10.1038/nature22360.

Selective impairment of peripheral regulatory T-cell differentiation is found to result in spontaneous allergic T H 2-type inflammation in the intestine and lungs, demonstrating the functional heterogeneity of regulatory T cells generated in the thymus and extrathymically in controlling immune mediated inflammation and disease. T-cell control of inflammation Regulatory T (T reg ) cells generated in the periphery are shown to have a distinct non-redundant function compared with T reg cells that differentiate in the thymus. Selective impairment of peripheral T reg differentiation results in spontaneous allergic T H 2 type inflammation in the intestine and lungs. This study in mice delineates the functional heterogeneity of T reg cells in controlling systemic mucosal inflammation and disease. A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation 1 . Regulatory T (T reg ) cells prevent systemic and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus (tT reg cells) and in the periphery (induced (i)T reg cells), and their dual origin implies a division of labour between tT reg and iT reg cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of iT reg cells in mice did not lead to unprovoked multi-organ autoimmunity, exacerbation of induced tissue-specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 (T H 1) and T H 17 cells. However, mice deficient in iT reg cells spontaneously developed pronounced T H 2-type pathologies at mucosal sites—in the gastrointestinal tract and lungs—with hallmarks of allergic inflammation and asthma. Furthermore, iT reg -cell deficiency altered gut microbial communities. These results suggest that whereas T reg cells generated in the thymus appear sufficient for control of systemic and tissue-specific autoimmunity, extrathymic differentiation of T reg cells affects commensal microbiota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces.

A balance between pro- and anti-inflammatory mechanisms at mucosal interfaces, which are sites of constitutive exposure to microbes and non-microbial foreign substances, allows for efficient protection against pathogens yet prevents adverse inflammatory responses associated with allergy, asthma and intestinal inflammation (1). Regulatory T ([T.sub.reg]) cells prevent systemic and tissue-specific autoimmunity and inflammatory lesions at mucosal interfaces. These cells are generated in the thymus ([tT.sub.reg] cells) and in the periphery (induced (i)[T.sub.reg] cells), and their dual origin implies a division of labour between [tT.sub.reg] and [iT.sub.reg] cells in immune homeostasis. Here we show that a highly selective blockage in differentiation of [iT.sub.reg] cells in mice did not lead to unprovoked multiorgan autoimmunity, exacerbation of induced tissue-specific autoimmune pathology, or increased pro-inflammatory responses of T helper 1 ([T.sub.H]1) and [T.sub.H]17 cells. However, mice deficient in [iT.sub.reg] cells spontaneously developed pronounced [T.sub.H]2-type pathologies at mucosal sites--in the gastrointestinal tract and lungs--with hallmarks of allergic inflammation and asthma. Furthermore, [iT.sub.reg]-cell deficiency altered gut microbial communities. These results suggest that whereas [T.sub.reg] cells generated in the thymus appear sufficient for control of systemic and tissue-specific autoimmunity, extrathymic differentiation of [T.sub.reg] cells affects commensal micro-biota composition and serves a distinct, essential function in restraint of allergic-type inflammation at mucosal interfaces.

Nature 546, 421–425 (2017); 10.1038/nature22360 In this Letter, author Alejandra Mendoza was incorrectly spelled Alejandra Medoza. The original Letter has been corrected online.