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Innate lymphoid cells (ILCs) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues thus far has been unclear. We found that in the lymphoid and nonlymphoid organs of adult mice, ILCs are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis and during acute helminth infection. However, at later time points after infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILCs are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme \"sedentary\" lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function.

In mice, provision of butyrate—a short-chain fatty acid produced by commensal microorganisms during starch fermentation—facilitates extrathymic generation and differentiation of Foxp3 + regulatory T cells, demonstrating that metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. Bacterial butyrate influences immune balance Several lines of evidence indicate that subsets of commensal microbes shape the gut immune system. For instance, colonization with Clostridia promotes extrathymic generation of regulatory T (T reg ) cells that have a central role in the suppression of inflammatory and allergic responses. However, the molecular basis of such microbe-mediated T reg induction remains unknown. Two papers in this issue of Nature show that the colonic microbial fermentation product butyrate significantly accelerates the differentiation of colonic T reg cells and ameliorates colitis in conjunction with an increase in histone H3 acetylation at the Foxp3 promoter. This finding links butyrate to the induction of functional T reg cells in the colonic mucosa, and also provides molecular insight into the therapeutic application of butyrate. Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (T reg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine 1 . Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory T reg or pro-inflammatory T helper 17 (T H 17) cells 2 , 3 , 4 , 5 , 6 , the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory T reg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of T reg cells. A boost in T reg -cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of T reg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic T reg -cell differentiation 1 , 7 . In addition to butyrate, de novo T reg -cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.

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.

Regulatory T cells need to express a diverse T-cell-receptor repertoire to control pathogenic self-reactive T cells; here it is shown that repertoire diversification depends on the intronic Foxp3 enhancer CNS3 acting at the regulatory T-cell-precursor stage to induce T-cell-receptor responsiveness to low-strength signals. T reg cell diversification mechanism Regulatory T cells (T reg cells) need to express a diverse T-cell receptor repertoire in order to control pathogenic self-reactive T cells that have survived negative selection in the thymus. Alexander Rudensky and colleagues show here that the repertoire diversification depends on the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3), acting at the T reg precursor stage, to enable induction of the Foxp3 gene in response to low-strength T-cell-receptor signals. T-cell receptor (TCR) signalling has a key role in determining T-cell fate. Precursor cells expressing TCRs within a certain low-affinity range for complexes of self-peptide and major histocompatibility complex (MHC) undergo positive selection and differentiate into naive T cells expressing a highly diverse self-MHC-restricted TCR repertoire. In contrast, precursors displaying TCRs with a high affinity for ‘self’ are either eliminated through TCR-agonist-induced apoptosis (negative selection) 1 or restrained by regulatory T (T reg ) cells, whose differentiation and function are controlled by the X-chromosome-encoded transcription factor Foxp3 (reviewed in ref. 2 ). Foxp3 is expressed in a fraction of self-reactive T cells that escape negative selection in response to agonist-driven TCR signals combined with interleukin 2 (IL-2) receptor signalling. In addition to T reg cells, TCR-agonist-driven selection results in the generation of several other specialized T-cell lineages such as natural killer T cells and innate mucosal-associated invariant T cells 3 . Although the latter exhibit a restricted TCR repertoire, T reg cells display a highly diverse collection of TCRs 4 , 5 , 6 . Here we explore in mice whether a specialized mechanism enables agonist-driven selection of T reg cells with a diverse TCR repertoire, and the importance this holds for self-tolerance. We show that the intronic Foxp3 enhancer conserved noncoding sequence 3 (CNS3) acts as an epigenetic switch that confers a poised state to the Foxp3 promoter in precursor cells to make T reg cell lineage commitment responsive to a broad range of TCR stimuli, particularly to suboptimal ones. CNS3-dependent expansion of the TCR repertoire enables T reg cells to control self-reactive T cells effectively, especially when thymic negative selection is genetically impaired. Our findings highlight the complementary roles of these two main mechanisms of self-tolerance.

While regulatory T (T reg ) cells are traditionally viewed as professional suppressors of antigen presenting cells and effector T cells in both autoimmunity and cancer, recent findings of distinct T reg cell functions in tissue maintenance suggest that their regulatory purview extends to a wider range of cells and is broader than previously assumed. To elucidate tumoral T reg cell ‘connectivity’ to diverse tumor-supporting accessory cell types, we explored immediate early changes in their single-cell transcriptomes upon punctual T reg cell depletion in experimental lung cancer and injury-induced inflammation. Before any notable T cell activation and inflammation, fibroblasts, endothelial and myeloid cells exhibited pronounced changes in their gene expression in both cancer and injury settings. Factor analysis revealed shared T reg cell-dependent gene programs, foremost, prominent upregulation of VEGF and CCR2 signaling-related genes upon T reg cell deprivation in either setting, as well as in T reg cell-poor versus T reg cell-rich human lung adenocarcinomas. Accordingly, punctual T reg cell depletion combined with short-term VEGF blockade showed markedly improved control of PD-1 blockade-resistant lung adenocarcinoma progression in mice compared to the corresponding monotherapies, highlighting a promising factor-based querying approach to elucidating new rational combination treatments of solid organ cancers. Single-cell and spatial analyses of conserved regulatory T (T reg ) cell-dependent transcriptional states of diverse accessory cell types in mouse and human lung cancer suggest rational T reg cell targeting-based combination therapy for PD-1 blockade-resistant tumors.

Regulatory T (Treg) cells are a subset of T cells essential for preventing autoimmunity. Treg cell identity is specified by the transcription factor Foxp3, which is stably expressed exclusively in this lineage. The importance of Treg cells for organismal health and of Foxp3 for Treg cell function is demonstrated by the severe diseases resulting from depletion of Treg cells or inactivating mutations in Foxp3. Treg cells arise from precursors which acquire Foxp3 expression in the thymus or in the periphery. Thereafter, these newly generated Treg cells circulate through or establish long-term residence in a wide variety of lymphoid and non-lymphoid tissues, where they suppress inflammation, support organ function, and ensure tolerance to environmental and microbiota-derived antigens. How thymic and extra-thymic Treg cell differentiation processes ensure the emergence of the variety of cells able to carry out such diverse functions, and how their subsequent activation and differentiation further supports this diversification is imperfectly understood. In one set of studies, we demonstrated that an enhancer of Foxp3, Conserved Non-coding Sequence 0 (CNS0), enabled interleukin-2—STAT5 dependent induction of Foxp3 expression during thymic Treg cell differentiation. This activity supported the diversification of the Treg cell T cell receptor (TCR) repertoire and provided an anti-inflammatory buffer during autoimmune disease. In another set of studies, we investigated how extra-thymic Treg cell differentiation, facilitated by another enhancer of Foxp3, CNS1, impacts organismal homeostasis. We found that CNS1-dependent Treg cells supported the engraftment of specific colonic microbes by restraining immune reactivity during microbial community assembly. The engraftment of these bacteria, as well as the acute control of immune reactivity ensured optimal function of the intestinal tissue and prevented spontaneous immune activation later in life. Finally, we studied the differentiation of mature Treg cells after activation in the periphery, specifically focusing on two distinct specialized subsets of Treg cells in the colon. We found that reduced TCR signaling favored the adoption of one fate, suggesting that differential regulation of a major signaling pathway allows specialization of Treg cells in non-lymphoid tissues. Together, our studies elucidated novel mechanisms of differentiation and the function of thymic and extrathymic Treg cells.

Innate lymphoid cells (ILC) contribute to barrier immunity, tissue homeostasis, and immune regulation at various anatomical sites throughout the body. How ILCs maintain their presence in lymphoid and peripheral tissues is currently unknown. We found that in the lymphoid and non-lymphoid organs of adult mice, ILC are tissue-resident cells that were maintained and expanded locally under physiologic conditions, upon systemic perturbation of immune homeostasis, and during acute helminth infection. However, at later time points post-infection, cells from hematogenous sources helped to partially replenish the pool of resident ILCs. Thus, ILC are maintained by self-renewal in broadly different microenvironments and physiological settings. Such an extreme “sedentary” lifestyle is consistent with the proposed roles of ILCs as sentinels and local keepers of tissue function.