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The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ Tregs in tumors are not well known. High-dimensional single-cell profiling of T cells from chemotherapy-naive individuals with non-small-cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity. In contrast to the IRF4- counterparts, IRF4+ Tregs expressed a vast array of suppressive molecules, and their presence correlated with multiple exhausted subpopulations of T cells. Integration of transcriptomic and epigenomic data revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for immunosuppression in tumors. Accordingly, deletion of Irf4 exclusively in Tregs resulted in delayed tumor growth in mice while the abundance of IRF4+ Tregs correlated with poor prognosis in patients with multiple human cancers. Thus, a common mechanism underlies immunosuppression in the tumor microenvironment irrespective of the tumor type.

Foxp3 + regulatory T cells (T reg 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 T reg cells to constrain microbiota-dependent interleukin (IL)-17–producing helper T cell (T H 17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal T reg cell populations, including RORγt + T reg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled T reg 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 T reg cells. c-Maf deficiency in T reg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal T H 17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal T reg cells, which is essential for the establishment of host–microbe symbiosis. An intricately linked homeostasis exists between the gut microbiome and host immune system. Scheffold and colleagues show that intestinal T reg cells upregulate the transcription factor c-Maf in response to specific signals from the gut microenvironment to establish host–microbiota homeostasis.

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.

The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1-deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte-associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.

Expression of microRNA miR‐181a/b‐1 is critical for intrathymic development of invariant natural killer T (iNKT) cells. However, the underlying mechanism has remained a matter of debate. On the one hand, growing evidence suggested that miR‐181a/b‐1 is instrumental in setting T‐cell receptor (TCR) signaling threshold and thus permits agonist selection of iNKT cells through high‐affinity TCR ligands. On the other hand, alterations in metabolic fitness mediated by miR‐181a/b‐1‐dependent dysregulation of phosphatase and tensin homolog (Pten) have been proposed to cause the iNKT‐cell defect in miR‐181‐a/b‐1‐deficient mice. To re‐assess the hypothesis that modulation of TCR signal strength is the key mechanism by which miR‐181a/b‐1 controls the development of iNKT cells, we generated miR‐181a/b‐1‐deficient mice expressing elevated levels of a Vα14Jα18 TCRα chain. In these mice, development of iNKT cells was fully restored. Furthermore, both subset distribution of iNKT cells as well as TCR Vβ repertoire were independent of the presence of miR‐181a/b‐1 once a Vα14Jα18 TCRα chain was overexpressed. Finally, levels of Pten protein were similar in Vα14Jα18 transgenic mice irrespective of their miR‐181a/b‐1 status. Collectively, our data support a model in which miR‐181 promotes development of iNKT cells primarily by generating a permissive state for agonist selection with alterations in metabolic fitness possibly constituting a secondary effect.

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.

Foxp3.sup.+ regulatory T cells (T.sub.reg 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 T.sub.reg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (T.sub.H17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal T.sub.reg cell populations, including ROR[gamma]t.sup.+ T.sub.reg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled T.sub.reg 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 T.sub.reg cells. c-Maf deficiency in T.sub.reg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal T.sub.H17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal T.sub.reg cells, which is essential for the establishment of host-microbe symbiosis.

Humanized mouse models have become increasingly valuable tools to study human hematopoiesis and infectious diseases. However, human T-cell differentiation remains inefficient. We generated mice expressing human interleukin-7 (IL-7), a critical growth and survival factor for T cells, under the control of murine IL-7 regulatory elements. After transfer of human cord blood-derived hematopoietic stem and progenitor cells, transgenic mice on the NSGW41 background, termed NSGW41hIL7, showed elevated and prolonged human cellularity in the thymus while maintaining physiological ratios of thymocyte subsets. As a consequence, numbers of functional human T cells in the periphery were increased without evidence for pathological lymphoproliferation or aberrant expansion of effector or memory-like T cells. We conclude that the novel NSGW41hIL7 strain represents an optimized mouse model for humanization to better understand human T-cell differentiation in vivo and to generate a human immune system with a better approximation of human lymphocyte ratios.

This article, based on research conducted in Jordan, discusses how favoritism affects the business climate. Jordan's business climate is mediocre in international and regional comparison, making it insufficient in light of the country's small domestic market. Businesspeople consider the complexity of administrative procedures to be a main problem for investors, along with a lack of fairness and predictability in administrative decisions. Favoritism, which is referred to as \"using wasta,\" (connections) contributes substantially to both problems. Investors with good wasta can speed up procedures and get exclusive access to services and information. They can even influence legislation to their advantage. Perhaps even more problematic, entrepreneurs tend to invest their time and money in social relations rather than in productive capital, because their success depends on their wasta rather than the quality of their products. Many Jordanians are aware of these problems. Nevertheless they keep using wasta for at least four reasons. First, they do not see any alternative for achieving their goals. Second, people go on using their wasta as long as everybody else does the same. Third, many Jordanians associate the use of wasta with cherished values, such as solidarity or loyalty, i.e. they believe that the use of wasta is part of their culture. Fourth, Jordan's administrative and political system lacks transparency and accountability on all levels.