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Differentiation and homeostasis of Foxp3 + regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells. The transcription factor Bach2 is critical for T cell differentiation, but how it functions in Treg cells is unclear. Here the authors use a Treg-specific mouse model to show that Bach2 controls homeostasis and function of Treg cells by limiting DNA accessibility and activity of IRF4 in response to TCR signaling.

Chronic stimulation of CD8 + T cells triggers exhaustion, a distinct differentiation state with diminished effector function. Exhausted cells exist in multiple differentiation states, from stem-like progenitors that are the key mediators of the response to checkpoint blockade, through to terminally exhausted cells. Due to its clinical relevance, there is substantial interest in defining the pathways that control differentiation and maintenance of these subsets. Here, we show that chronic antigen induces the anergy-associated transcription factor EGR2 selectively within progenitor exhausted cells in both chronic LCMV and tumours. EGR2 enables terminal exhaustion and stabilizes the exhausted transcriptional state by both direct EGR2-dependent control of key exhaustion-associated genes, and indirect maintenance of the exhausted epigenetic state. We show that EGR2 is a regulator of exhaustion that epigenetically and transcriptionally maintains the differentiation competency of progenitor exhausted cells. Exhausted T cells arise when chronic activation triggers functional defects. Here the authors show that chronic antigenic stimulation in both tumour and infection models induces the expression of EGR2, which drives and stabilises exhausted cell epigenetic and transcriptional identity.

IL-17-producing CD8 + (Tc17) cells are enriched in active lesions of patients with multiple sclerosis (MS), suggesting a role in the pathogenesis of autoimmunity. Here we show that amelioration of MS by dimethyl fumarate (DMF), a mechanistically elusive drug, associates with suppression of Tc17 cells. DMF treatment results in reduced frequency of Tc17, contrary to Th17 cells, and in a decreased ratio of the regulators RORC -to- TBX21 , along with a shift towards cytotoxic T lymphocyte gene expression signature in CD8 + T cells from MS patients. Mechanistically, DMF potentiates the PI3K-AKT-FOXO1-T-BET pathway, thereby limiting IL-17 and RORγt expression as well as STAT5-signaling in a glutathione-dependent manner. This results in chromatin remodeling at the Il17 locus. Consequently, T-BET-deficiency in mice or inhibition of PI3K-AKT, STAT5 or reactive oxygen species prevents DMF-mediated Tc17 suppression. Overall, our data disclose a DMF-AKT-T-BET driven immune modulation and suggest putative therapy targets in MS and beyond. Dimethyl fumarate (DMF) is a therapy for multiple sclerosis (MS) with undetermined mechanism of action. Here the authors find that clinical response to DMF associates with decrease in IL-17-producing CD8 +  T cells (Tc17), delineate molecular pathways involved, and show that DMF suppresses Tc17 pathogenicity in a mouse model of MS.

CD8 + T cells responding to chronic infections or tumors acquire an ‘exhausted’ state associated with elevated expression of inhibitory receptors, including PD-1, and impaired cytokine production. Exhausted T cells are continuously replenished by T cells with precursor characteristics that self-renew and depend on the transcription factor TCF1; however, their developmental requirements are poorly understood. In the present study, we demonstrate that high antigen load promoted the differentiation of precursor T cells, which acquired hallmarks of exhaustion within days of infection, whereas early effector cells retained polyfunctional features. Early precursor T cells showed epigenetic imprinting characteristic of T cell receptor–dependent transcription factor binding and were restricted to the generation of cells displaying exhaustion characteristics. Transcription factors BACH2 and BATF were key regulators with opposing functions in the generation of early precursor T cells. Overall, we demonstrate that exhaustion manifests first in TCF1 + precursor T cells and is propagated subsequently to the pool of antigen-specific T cells. The developmental timing for exhaustion is still obscure. Kallies and colleagues demonstrate that CD8 + T cell ‘exhaustion’ actually begins in the less-differentiated TCF1 + ‘precursor’ T cell pool during chronic viral infections.

Adipose tissue is an energy store and a dynamic endocrine organ 1 , 2 . In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism 3 , 4 . Impaired VAT function—for example, in obesity—is associated with insulin resistance and type 2 diabetes 5 , 6 . Regulatory T (T reg ) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT 7 – 9 . Here we uncover pronounced sexual dimorphism in T reg cells in the VAT. Male VAT was enriched for T reg cells compared with female VAT, and T reg cells from male VAT were markedly different from their female counterparts in phenotype, transcriptional landscape and chromatin accessibility. Heightened inflammation in the male VAT facilitated the recruitment of T reg cells via the CCL2–CCR2 axis. Androgen regulated the differentiation of a unique IL-33-producing stromal cell population specific to the male VAT, which paralleled the local expansion of T reg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident T reg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in T reg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation. Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.

Obesity-associated inflammation is restrained by regulatory T cells present in visceral fat. Kallies and colleagues show interleukin 33 and the transcription factors BATF and IRF4 are necessary to maintain visceral adipose tissue T reg cells. Foxp3 + regulatory T (T reg ) cells in visceral adipose tissue (VAT-T reg cells) are functionally specialized tissue-resident cells that prevent obesity-associated inflammation and preserve insulin sensitivity and glucose tolerance. Their development depends on the transcription factor PPAR-γ; however, the environmental cues required for their differentiation are unknown. Here we show that interleukin 33 (IL-33) signaling through the IL-33 receptor ST2 and myeloid differentiation factor MyD88 is essential for development and maintenance of VAT-T reg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-T reg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-T reg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue T reg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-T reg cell homeostasis.

Using genetic approaches and transcriptional profiling, Kallies and colleagues reveal a common program of effector CD8 + T cell differentiation that is regulated by the cooperation of IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. T cell responses are guided by cytokines that induce transcriptional regulators, which ultimately control differentiation of effector and memory T cells. However, it is unknown how the activities of these molecular regulators are coordinated and integrated during the differentiation process. Using genetic approaches and transcriptional profiling of antigen-specific CD8 + T cells, we reveal a common program of effector differentiation that is regulated by IL-2 and IL-12 signaling and the combined activities of the transcriptional regulators Blimp-1 and T-bet. The loss of both T-bet and Blimp-1 leads to abrogated cytotoxic function and ectopic IL-17 production in CD8 + T cells. Overall, our data reveal two major overlapping pathways of effector differentiation governed by the availability of Blimp-1 and T-bet and suggest a model for cytokine-induced transcriptional changes that combine, quantitatively and qualitatively, to promote robust effector CD8 + T cell differentiation.

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.

Mutations in the RNA-binding protein roquin-1 are known to result in humoral autoimmunity. Heissmeyer and colleagues show that MALT1 cleavage of roquin and regnase-1 downstream of TCR signaling releases cooperatively repressed targets to promote T H 17 cell differentiation Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T FH cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T H 17 subset of helper T cells in the lungs. Roquin inhibited T H 17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T H 17 cell–promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T H 17 differentiation.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-2251-7