Microbiota-mediated effects on the host immune response facilitate colonization resistance against pathogens. However, it is unclear whether and how the host immune response can regulate the ...microbiota to mediate colonization resistance. ID2, an essential transcriptional regulator for the development of innate lymphoid cell (ILC) progenitors, remains highly expressed in differentiated ILCs with unknown function. Using conditionally deficient mice in which ID2 is deleted from differentiated ILC3s, we observed that these mutant mice exhibited greatly impaired gut colonization resistance against Citrobacter rodentium. Utilizing gnotobiotic hosts, we showed that the ID2-dependent early colonization resistance was mediated by interleukin-22 (IL-22) regulation of the microbiota. In addition to regulating development, ID2 maintained homeostasis of ILC3s and controlled IL-22 production through an aryl hydrocarbon receptor (AhR) and IL-23 receptor pathway. Thus, ILC3s can mediate immune surveillance, which constantly maintains a proper microbiota, to facilitate early colonization resistance through an ID2-dependent regulation of IL-22.
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•ID2 is essential to mediate colonization resistance against C. rodentium•Continued expression of ID2 is required for the homeostasis of ILC3s•ID2-E2A interaction regulates ILC3s producing IL-22 through the AhR and IL-23R pathway•IL-22 from ILC3s controls colonization resistance through regulating the microbiota
Group 3 innate lymphoid cells (ILC3s) are important for protection from gut pathogen infection. Fu and colleagues show that ID2-dependent ILC3s produce IL-22 and limit early colonization of pathogen through homeostasis of the microbiota.
E and ID proteins branch out Kee, Barbara L
Nature reviews. Immunology,
200903, 2009-Mar, 2009-3-00, 20090301, Letnik:
9, Številka:
3
Journal Article
Recenzirano
E and inhibitor of DNA binding (ID) proteins are transcriptional regulators that function in many developmental processes in vertebrates and invertebrates. One subset of E proteins, the E2A proteins, ...have a central role in the transcriptional regulatory networks that promote commitment to and differentiation of the B- and T-cell lineages, and their function in these lineages is modulated by ID proteins. In this Review, I discuss recent studies that reveal a more extensive role for E and ID proteins in the transcriptional networks that drive the differentiation of many lymphoid lineages, as well as new functions for these proteins in haematopoietic stem cells and their multipotent, but lymphoid-primed, progeny.
Multiple transcription factors guide the development of mature functional natural killer (NK) cells, yet little is known about their function. We used global gene expression and genome-wide binding ...analyses combined with developmental and functional studies to unveil three roles for the ETS1 transcription factor in NK cells. ETS1 functions at the earliest stages of NK cell development to promote expression of critical transcriptional regulators including T-BET and ID2, NK cell receptors (NKRs) including NKp46, Ly49H, and Ly49D, and signaling molecules essential for NKR function. As a consequence, Ets1−/− NK cells fail to degranulate after stimulation through activating NKRs. Nonetheless, these cells are hyperresponsive to cytokines and have characteristics of chronic stimulation including increased expression of inhibitory NKRs and multiple activation-associated genes. Therefore, ETS1 regulates a broad gene expression program in NK cells that promotes target cell recognition while limiting cytokine-driven activation.
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► The essential NK cell genes Tbx21 and Idb2 are direct targets of ETS1 ► ETS1 is required for expression and function of multiple activating NK cell receptors ► ETS1 prevents chronic activation of NK cells ► ETS1-deficient NK cells are hyperresponsive to interleukin 15
Innate lymphoid cells (ILCs) are a family of immune effector cells that have important roles in host defense, metabolic homeostasis and tissue repair but can also contribute to inflammatory diseases ...such as asthma and colitis. These cells can be categorized into three groups on the basis of the transcription factors that direct their function and the cytokines they produce, which parallel the effector functions of T lymphocytes. The hierarchy of cell-fate-restriction events that occur as common lymphoid progenitors become committed to each of the ILC lineages further underscores the relationship between these innate immune cells and T lymphocytes. In this Review we discuss the developmental program of ILCs and transcription factors that guide ILC lineage specification and commitment.
EBF1 is a pioneer transcription factor involved in B lymphocyte specification. In this issue of Immunity, Wang et al. localize EBF1's pioneering activity to a prion-like domain that mediates ...recruitment of the nucleosome remodeler Brg1 and FUS-assisted liquid-liquid phase separation.
The expression of lineage-associated genes, as well as the survival and expansion of committed B cell progenitors, is controlled by multiple transcriptional regulators and growth-factor receptors. ...Whereas certain DNA-binding proteins, such as Ikaros and PU.1, are required primarily for the formation of more primitive lymphoid progenitors, other factors such as E2A and EBF1 have more direct roles in specifying the B cell-specific gene-expression program. Further, Pax5 functions to promote B cell commitment by repressing lineage-inappropriate gene expression and reinforcing B cell-specific gene expression. In this review, we focus on recent studies that have revealed that instead of a simple transcriptional hierarchy, efficient B cell commitment and differentiation requires the combinatorial activity of multiple transcription factors in a complex gene regulatory network.
T Lymphocyte Acute Lymphoblastic Leukemia (ALL) is an aggressive disease arising from transformation of T lymphocytes during their development. The mutation spectrum of T-ALL has revealed critical ...regulators of the growth and differentiation of normal and leukemic T lymphocytes. Approximately, 60% of T-ALLs show aberrant expression of the hematopoietic stem cell-associated helix-loop-helix transcription factors TAL1 and LYL1. TAL1 and LYL1 function in multiprotein complexes that regulate gene expression in T-ALL but they also antagonize the function of the E protein homodimers that are critical regulators of T cell development. Mice lacking E2A, or ectopically expressing TAL1, LYL1, or other inhibitors of E protein function in T cell progenitors, also succumb to an aggressive T-ALL-like disease highlighting that E proteins promote T cell development and suppress leukemogenesis. In this review, we discuss the role of E2A in T cell development and how alterations in E protein function underlie leukemogenesis. We focus on the role of TAL1 and LYL1 and the genes that are dysregulated in
T cell progenitors that contribute to human T-ALL. These studies reveal novel mechanisms of transformation and provide insights into potential therapeutic targets for intervention in this disease.
•A minor subset of iNKT cells derives from DN cells, bypassing the DP stage.•Conformational changes in iNKT TCR regulate iNKT cell fate.•Adipose tissue resident NKT10 cells originate from the ...thymus.•Global transcriptional and epigenetic profiles vary among iNKT cell subsets.•Epigenetic regulators control chromatin accessibility near lineage-specific genes.
Invariant Natural Killer T (iNKT) cells are a heterogeneous innate T cell population that recognizes lipid antigens. Despite the monospecific nature of their T cell receptor, iNKT cells differentiate into stable sublineages during thymic development, before foreign antigen encounter. How iNKT cell subsets acquire and maintain their functional programs is a central question in innate lymphocyte biology. Global transcriptional and epigenetic profiling of iNKT subsets has provided insights into the internal wiring of these subsets that defines their identity. Comparison of the iNKT transcriptional programs with those of other adaptive and innate lymphocyte lineages revealed common core regulatory circuits that may dictate effector functions. In this review, we summarize recent advances on the molecular mechanisms involved in iNKT cell development.
The Id2 transcriptional repressor is essential for development of natural killer (NK) cells, lymphoid tissue-inducing (LTi) cells, and secondary lymphoid tissues. Id2 was proposed to regulate NK and ...LTi lineage specification from multipotent progenitors through suppression of E proteins. We report that NK cell progenitors are not reduced in the bone marrow (BM) of Id2(-/-) mice, demonstrating that Id2 is not essential for NK lineage specification. Rather, Id2 is required for development of mature (m) NK cells. We define the mechanism by which Id2 functions by showing that a reduction in E protein activity, through deletion of E2A, overcomes the need for Id2 in development of BM mNK cells, LTi cells, and secondary lymphoid tissues. However, mNK cells are not restored in the blood or spleen of Id2(-/-)E2A(-/-) mice, suggesting a role for Id2 in suppression of alternative E proteins after maturation. Interestingly, the few splenic mNK cells in Id2(-/-) and Id2(-/-)E2A(-/-) mice have characteristics of thymus-derived NK cells, which develop in the absence of Id2, implying a differential requirement for Id2 in BM and thymic mNK development. Our findings redefine the essential functions of Id2 in lymphoid development and provide insight into the dynamic regulation of E and Id proteins during this process.
Abstract
Innate-like lymphocytes are a subset of lymphoid cells that function as a first line of defense against microbial infection. These cells are activated by proinflammatory cytokines or broadly ...expressed receptors and are able to rapidly perform their effector functions owing to a uniquely primed chromatin state that is acquired as a part of their developmental program. These cells function in many organs to protect against disease, but they release cytokines and cytotoxic mediators that can also lead to severe tissue pathologies. Therefore, harnessing the capabilities of these cells for therapeutic interventions will require a deep understanding of how these cells develop and regulate their effector functions. In this review we discuss recent advances in the identification of the transcription factors and the genomic regions that guide the development and function of invariant NKT cells and we highlight related mechanisms in other innate-like lymphocytes.
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