Two regulatory T cell populations in the visceral adipose tissue shape systemic metabolism.

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.

Early precursor T cells establish and propagate T cell exhaustion in chronic infection.

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.

c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis.

Foxp3+ regulatory T cells (Treg cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal Treg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (TH17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal Treg cell populations, including RORγt+ Treg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled Treg cell-derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal Treg cells. c-Maf deficiency in Treg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal TH17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal Treg cells, which is essential for the establishment of host-microbe symbiosis.

Transcriptional and hormonal control of adipose Treg heterogeneity and function.

Adipose tissue stores excess energy and produces a broad range of factors that regulate multiple physiological processes including systemic energy homeostasis. Visceral adipose tissue (VAT) plays a particularly important role in glucose metabolism as its endocrine function underpins food uptake and energy expenditure. Caloric excess triggers VAT inflammation which can impair insulin sensitivity and cause metabolic deregulation. Regulatory T cells (Tregs) that reside in the VAT suppress inflammation and protect from metabolic disease. The cellular components of VAT and its secretory products play a vital role in fostering the differentiation and maintenance of VAT Tregs. Critically, the physiology and inflammatory tone of VAT exhibit sex-specific disparities, resulting in substantial VAT Treg heterogeneity. Indeed, cytokines and sex hormones promote the differentiation of distinct populations of mature VAT Tregs, each characterized by unique phenotypes, homeostatic requirements, and functions. This review focuses on key findings that have significantly advanced our understanding of VAT Treg biology and the current state of the field, while also discussing open questions that require further exploration.

The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells.

Foxp3(+) regulatory T (Treg) cells in visceral adipose tissue (VAT-Treg 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-Treg cells and sustains their transcriptional signature. Furthermore, the transcriptional regulators BATF and IRF4 were necessary for VAT-Treg differentiation through direct regulation of ST2 and PPAR-γ expression. IL-33 administration induced vigorous population expansion of VAT-Treg cells, which tightly correlated with improvements in metabolic parameters in obese mice. Human omental adipose tissue Treg cells also showed high ST2 expression, suggesting an evolutionarily conserved requirement for IL-33 in VAT-Treg cell homeostasis.

Sex-specific adipose tissue imprinting of regulatory T cells.

Adipose tissue is an energy store and a dynamic endocrine organ1,2. In particular, visceral adipose tissue (VAT) is critical for the regulation of systemic metabolism3,4. Impaired VAT function-for example, in obesity-is associated with insulin resistance and type 2 diabetes5,6. Regulatory T (Treg) cells that express the transcription factor FOXP3 are critical for limiting immune responses and suppressing tissue inflammation, including in the VAT7-9. Here we uncover pronounced sexual dimorphism in Treg cells in the VAT. Male VAT was enriched for Treg cells compared with female VAT, and Treg 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 Treg 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 Treg cells. Sex hormones also regulated VAT inflammation, which shaped the transcriptional landscape of VAT-resident Treg cells in a BLIMP1 transcription factor-dependent manner. Overall, we find that sex-specific differences in Treg cells from VAT are determined by the tissue niche in a sex-hormone-dependent manner to limit adipose tissue inflammation.

A non-canonical function of Ezh2 preserves immune homeostasis.

Enhancer of zeste 2 (Ezh2) mainly methylates lysine 27 of histone-H3 (H3K27me3) as part of the polycomb repressive complex 2 (PRC2) together with Suz12 and Eed. However, Ezh2 can also modify non-histone substrates, although it is unclear whether this mechanism has a role during development. Here, we present evidence for a chromatin-independent role of Ezh2 during T-cell development and immune homeostasis. T-cell-specific depletion of Ezh2 induces a pronounced expansion of natural killer T (NKT) cells, although Ezh2-deficient T cells maintain normal levels of H3K27me3. In contrast, removal of Suz12 or Eed destabilizes canonical PRC2 function and ablates NKT cell development completely. We further show that Ezh2 directly methylates the NKT cell lineage defining transcription factor PLZF, leading to its ubiquitination and subsequent degradation. Sustained PLZF expression in Ezh2-deficient mice is associated with the expansion of a subset of NKT cells that cause immune perturbation. Taken together, we have identified a chromatin-independent function of Ezh2 that impacts on the development of the immune system.

The Regulatory T Cell: Jack-Of-All-Trades.

Foxp3(+) regulatory T (Treg) cells suppress auto-reactive and inflammatory T cells to maintain immune homeostasis. In a recent study, Rudensky and colleagues demonstrate the ability of Treg cells to facilitate tissue repair, a non-canonical Treg cell function accomplished by amphiregulin and mediated by cytokines interleukin (IL)-18 and IL-33.

NF-κB subunit specificity in hemopoiesis.

Although the diverse functions served by the nuclear factor-κB (NF-κB) pathway in virtually all cell types are typically employed to deal with stress responses, NF-κB transcription factors also play key roles in the development of hemopoietic cells. This review focuses on how NF-κB transcription factors control various aspects of thymic T-cell and myeloid cell differentiation that include its roles in hemopoietic precursors, conventional αß T cells, CD4(+) regulatory T cells, natural killer T cells, γδ T cells, macrophages, and dendritic cells.

IL-27 paves different roads to Tr1.

Tr1 cells are non-Foxp3-expressing regulatory CD4(+) T cells that execute suppressor functions by secreting the anti-inflammatory cytokine IL-10. Differentiation of this T-cell subset is facilitated by the heterodimeric cytokine IL-27, which can activate transcription factors such as c-Maf and Ahr to positively regulate the differentiation of Tr1 cells and their IL-10 production. In this issue of the European Journal of Immunology, an alternate transcriptional network regulated by IL-27 to induce IL-10 production in Tr1 cells is reported by Iwasaki et al. [Eur. J. Immunol. 2013. 43: 1063-1073]. This study shows that IL-27 initiates tandem activation of the transcription factors STAT3 and Egr-2 to induce il10 in Tr1 cells in a Blimp1-dependent fashion. These findings indicate a c-Maf/Ahr independent mechanism that activates IL-10 production by Tr1 cells and suggest that Il10 induction may depend on both the cytokine environment and the molecular context. Thus, Tr1 cells may be another example of the remarkable plasticity of CD4(+) T cells and indeed may not constitute a separate lineage of CD4(+) T cells but rather represent a developmental endpoint of several T helper cell differentiation pathways.

Role reversals: non-canonical roles for immune and non-immune cells in the gut.

The intestine is home to an intertwined network of epithelial, immune, and neuronal cells as well as the microbiome, with implications for immunity, systemic metabolism, and behavior. While the complexity of this microenvironment has long since been acknowledged, recent technological advances have propelled our understanding to an unprecedented level. Notably, the microbiota and non-immune or structural cells have emerged as important conductors of intestinal immunity, and by contrast, cells of both the innate and adaptive immune systems have demonstrated non-canonical roles in tissue repair and metabolism. This review highlights recent works in the following two streams: non-immune cells of the intestine performing immunological functions; and traditional immune cells exhibiting non-immune functions in the gut.

Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice.

Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.

Local administration of regulatory T cells promotes tissue healing.

Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.

Modulating T regulatory cells in cancer: how close are we?

Regulatory T cells (Tregs) are a specialized subset of CD4 T cells that have an indispensable role in maintaining immune homeostasis and tolerance. Although studies in mice and humans have clearly highlighted that the absence of these cells results in severe autoimmunity and inflammation, increased Treg numbers and/or function is not always beneficial. This is best exemplified in certain cancers where increased Tregs promote cancer progression by interfering with immune surveillance. Conversely, in other types of cancers that have an inflammatory component, Tregs can inhibit cancer progression by dampening inflammation. In this review article, we provide a historical perspective of the discovery of Tregs, followed by a summary of the existing literature on the role of Tregs in malignancy.

Thymic regulatory T cell development: role of signalling pathways and transcription factors.

Regulatory T cells (Tregs) are a subset of CD4 T cells that are key mediators of immune tolerance. Most Tregs develop in the thymus. In this review we summarise recent findings on the role of diverse signalling pathways and downstream transcription factors in thymic Treg development.

Regulation of daunorubicin biosynthesis in Streptomyces peucetius - feed forward and feedback transcriptional control.

Streptomyces are a major group of soil bacteria that produce wide range of bioactive compounds including antibiotics. Daunorubicin is a chemotherapeutic agent for treatment of certain types of cancer, which is produced as a secondary metabolite by S. peucetius. Owing to the significance of this drug in treating cancer, understanding the molecular mechanism of its biosynthesis will assist in the genetic manipulation of this strain for better drug yields. Additionally, the knowledge can also be applied to design hybrid antibiotics that can be made in vivo by transferring genes from one Streptomyces species to another. Biosynthesis of daunorubicin in S. peucetius is accomplished by the function of 30 enzyme-coding genes in a sequential and coordinated fashion. In addition to these enzymes, three transcriptional regulators DnrO, DnrN and DnrI regulate this multi-step process by forming a coherent feed forward loop regulatory circuit, consequently controlling the entire enzyme coding genes. Since daunorubicin is a DNA intercalating drug, maintaining an optimal intracellular drug concentration is pivotal to prevent self-toxicity. Commencement of daunorubicin biosynthesis also activates the feedback mechanisms mediated by the metabolite. At exceeding intracellular concentrations, daunorubicin intercalates into DNA sequences and impedes the binding of these transcription factors. This feedback repression is relieved by a group of self-resistance genes, which concurrently efflux the excess intracellular daunorubicin. This review will discuss the mechanistic role of each transcription factor and their interplay in initiating and maintaining the biosynthesis of daunorubicin in S. peucetius.