Although they are classically viewed as continuously recirculating through the lymphoid organs and blood, lymphocytes also establish residency in non-lymphoid tissues, most prominently at barrier ...sites, including the mucosal surfaces and skin. These specialized tissue-resident lymphocyte subsets span the innate-adaptive continuum and include innate lymphoid cells (ILCs), unconventional T cells (e.g., NKT, MAIT, γδ T cells, and CD8αα+ IELs), and tissue-resident memory T (TRM) cells. Although these diverse cell types differ in the particulars of their biology, they nonetheless exhibit important shared features, including a role in the preservation of tissue integrity and function during homeostasis, infection, and non-infectious perturbations. In this Review, we discuss the hallmarks of tissue-resident innate, innate-like, and adaptive lymphocytes, as well as their potential functions in non-lymphoid organs.
Tissue-resident lymphocyte subsets span the innate-adaptive continuum but nonetheless exhibit shared features that allow them to communicate with the tissue microenvironment and to preserve tissue integrity and function during homeostasis, infection, and non-infectious perturbations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regulatory T cells and Foxp3 Rudensky, Alexander Y.
Immunological reviews,
20/May , Volume:
241, Issue:
1
Journal Article
Peer reviewed
Open access
Regulatory T (Treg) cells play central role in regulation of immune responses to self‐antigens, allergens, and commensal microbiota as well as immune responses to infectious agents and tumors. ...Transcriptional factor Foxp3 serves as a lineage specification factor of Treg cells. Paucity of Treg cells due to loss‐of‐function mutations of the Foxp3 gene is responsible for highly aggressive, fatal, systemic immune‐mediated inflammatory lesions in mice and humans. Recent studies of Foxp3 expression and function provided critical novel insights into biology of Treg cells and into cellular mechanisms of the immune homeostasis.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Regulatory T (Treg) cells represent a distinct lineage of cells of the adaptive immune system indispensable for forestalling fatal autoimmune and inflammatory pathologies. The role of Treg cells as ...principal guardians of the immune system can be attributed to their ability to restrain all currently recognized major types of inflammatory responses through modulating the activity of a wide range of cells of the innate and adaptive immune system. This broad purview over immunity and inflammation is afforded by the multiple modes of action Treg cells exert upon their diverse molecular and cellular targets. Beyond the suppression of autoimmunity for which they were originally recognized, Treg cells have been implicated in tissue maintenance, repair, and regeneration under physiologic and pathologic conditions. Herein, we discuss the current and emerging understanding of Treg cell effector mechanisms in the context of the basic properties of Treg cells that endow them with such functional versatility.
Treg cells are an immunosuppressive lymphocyte subset essential for preventing autoimmunity. Dikiy and Rudensky review the mechanisms by which Treg cells prevent autoimmunity, mitigate inflammation, and support tissue function. They highlight how Treg cells identify cellular targets, localize to appropriate sites, become activated, and prevent intrinsic inflammatory responses in relation to the efficacy of their seemingly redundant mechanisms of action.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Innate lymphocytes - including natural killer cells and the recently discovered innate lymphoid cells - have crucial roles during infection, tissue injury and inflammation. Innate signals regulate ...the activation and homeostasis of innate lymphocytes. The contribution of the adaptive immune system to the coordination of innate lymphocyte responses is less well understood. In this Opinion article, we review our current understanding of the interactions between adaptive and innate lymphocytes, and propose a model in which T cells of the adaptive immune system function as antigen-specific sensors for the activation of innate lymphocytes to amplify and instruct local immune responses. We highlight the potential roles of regulatory and helper T cells in these processes, and discuss major questions in the emerging area of crosstalk between adaptive and innate lymphocytes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
MicroRNAs (miRNAs) are essential components of gene regulation, but identification of miRNA targets remains a major challenge. Most target prediction and discovery relies on perfect complementarity ...of the miRNA seed to the 3′ untranslated region (UTR). However, it is unclear to what extent miRNAs target sites without seed matches. Here, we performed a transcriptome-wide identification of the endogenous targets of a single miRNA—miR-155—in a genetically controlled manner. We found that approximately 40% of miR-155-dependent Argonaute binding occurs at sites without perfect seed matches. The majority of these noncanonical sites feature extensive complementarity to the miRNA seed with one mismatch. These noncanonical sites confer regulation of gene expression, albeit less potently than canonical sites. Thus, noncanonical miRNA binding sites are widespread, often contain seed-like motifs, and can regulate gene expression, generating a continuum of targeting and regulation.
► Differential CLIP-Seq reveals transcriptome-wide sites of miR-155 binding ► Many miR-155 binding sites are noncanonical and lack a perfect seed match ► Most noncanonical binding sites contain a mismatch to the canonical seed motif ► Noncanonical sites mediate gene regulation, albeit weaker than canonical sites
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Circadian rhythms regulate many aspects of physiology, ranging from sleep-wake cycles and metabolic parameters to susceptibility to infection. The molecular clock, with transcription factor BMAL1 at ...its core, controls both central and cell-intrinsic circadian rhythms. Using a circadian reporter, we observed dynamic regulation of clock activity in lymphocytes. However, its disruption upon conditional Bmal1 ablation did not alter T- or B-cell differentiation or function. Although the magnitude of interleukin 2 (IL-2) production was affected by the time of bacterial infection, it was independent of cell-intrinsic expression of BMAL1. The circadian gating of the IL-2 response was preserved in Bmal1-deficient T cells, despite a slight reduction in cytokine production in a competitive setting. Our results suggest that, contrary to the prevailing view, the adaptive immune response is not affected by the cell-intrinsic clock but is likely influenced by cell-extrinsic circadian cues operating across multiple cell types.
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•The cell-intrinsic circadian clock is dispensable for T- and B-cell development•TH17 differentiation is normal in mice with a T-cell-specific deletion of Bmal1•Circadian gating of IL-2 secretion is independent of the cell-intrinsic clock
The circadian clock regulates a multitude of processes, including behavior, metabolism, and immunity. Hemmers and Rudensky investigate the cell-intrinsic requirement for a circadian clock in adaptive immunity. Lymphocyte-specific deletion of Bmal1 revealed that the circadian clock is dispensable for normal differentiation and function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regulatory T (Treg) cells suppress immune responses to a broad range of non-microbial and microbial antigens and indirectly limit immune inflammation-inflicted tissue damage by employing multiple ...mechanisms of suppression. Here, we demonstrate that selective Treg cell deficiency in amphiregulin leads to severe acute lung damage and decreased blood oxygen concentration during influenza virus infection without any measureable alterations in Treg cell suppressor function, antiviral immune responses, or viral load. This tissue repair modality is mobilized in Treg cells in response to inflammatory mediator IL-18 or alarmin IL-33, but not by TCR signaling that is required for suppressor function. These results suggest that, during infectious lung injury, Treg cells have a major direct and non-redundant role in tissue repair and maintenance—distinct from their role in suppression of immune responses and inflammation—and that these two essential Treg cell functions are invoked by separable cues.
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•Treg cells serve as a major early source of amphiregulin during influenza infection•Amphiregulin expression in Treg cells is dispensable for their suppressor function•Amphiregulin deficiency in Treg cells results in severe damage of infected lungs•Treg cell production of amphiregulin is IL-18/IL-33 dependent but TCR independent
Regulatory T cells have a major direct and non-redundant role in tissue repair and maintenance that is distinct from their role in suppression of immune responses and inflammation and is invoked by a different set of cues.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regulatory T (Treg) cells, whose differentiation and function are controlled by X chromosome-encoded transcription factor Foxp3, are generated in the thymus (tTreg) and extrathymically (peripheral, ...pTreg), and their deficiency results in fatal autoimmunity. Here, we demonstrate that a Foxp3 enhancer, conserved noncoding sequence 1 (CNS1), essential for pTreg but dispensable for tTreg cell generation, is present only in placental mammals. CNS1 is largely composed of mammalian-wide interspersed repeats (MIR) that have undergone retrotransposition during early mammalian radiation. During pregnancy, pTreg cells specific to a model paternal alloantigen were generated in a CNS1-dependent manner and accumulated in the placenta. Furthermore, when mated with allogeneic, but not syngeneic, males, CNS1-deficient females showed increased fetal resorption accompanied by increased immune cell infiltration and defective remodeling of spiral arteries. Our results suggest that, during evolution, a CNS1-dependent mechanism of extrathymic differentiation of Treg cells emerged in placental animals to enforce maternal-fetal tolerance.
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► CNS1, a Foxp3 enhancer driving extrathymic Treg generation, appears in eutherians ► CNS1 facilitates accumulation of fetal alloantigen-specific Treg cells in decidua ► Increased fetal resorption during allogeneic pregnancy of CNS1-deficient females
Molecular phylogeny reveals that an enhancer for the transcription factor Foxp3, which is essential for the differentiation of a subset of regulatory T cells, is present only in placental mammals. These T cells are important for maternal tolerance of the fetus, presenting a potential explanation for the emergence of a mechanism of extrathymic differentiation of T regulatory cells during evolution.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In multicellular organisms, specialized functions are delegated to distinct cell types whose identity and functional integrity are maintained upon challenge. However, little is known about the ...mechanisms enabling lineage inheritance and their biological implications. Regulatory T (Treg) cells, which express the transcription factor Foxp3, suppress fatal autoimmunity throughout the lifespan of animals. Here, we show that a dedicated Foxp3 intronic element CNS2 maintains Treg cell lineage identity by acting as a sensor of the essential Treg cell growth factor IL-2 and its downstream target STAT5. CNS2 sustains Foxp3 expression during division of mature Treg cells when IL-2 is limiting and counteracts proinflammatory cytokine signaling that leads to the loss of Foxp3. CNS2-mediated stable inheritance of Foxp3 expression is critical for adequate suppression of diverse types of chronic inflammation by Treg cells and prevents their differentiation into inflammatory effector cells. The described mechanism may represent a general principle of the inheritance of differentiated cell states.
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•Cytokine signaling regulates heritable Foxp3 expression•Intronic element CNS2 sustains heritable Foxp3 expression in mature Treg•IL-2-STAT5 acts on CNS2 to counteract proinflammatory cytokine signaling•Critical roles of Treg fate heritability in physiological contexts
The identity of regulatory T (Treg) cells, whose differentiation and function is dependent on transcription factor Foxp3, is maintained by an intronic element during cell division when IL-2, an essential Treg cell differentiation factor, is limiting and upon exposure to proinflammatory cytokines that drive alternative effector T cell differentiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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