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A hierarchical Rorc(γt) cis-regulatory cascade orchestrates differentiation of RORγt⁺ innate immune cells [ChIP-seq]

ABSTRACT: Beyond its well-established role in type 3 immunity, RORγt+ innate immune cells are also essential for secondary lymphoid organ (SLO) formation and gut homeostasis. However, the transcriptional regulatory mechanisms governing RORγt expression in these cells, including ILC3s, LTi cells, and antigen-presenting cells (APCs), remain largely unknown. Here, we identify two key cis-regulatory elements within conserved non-coding sequences (CNS) 9 and 11 in the Rorc locus, which are sequentially utilized during their differentiation. Initially, Runx-binding sites in CNS11 establish chromatin accessibility as early as the HSC stage. Notably, disruption of this chromatin priming prevents subsequent transcriptional activation, thereby abolishing the initial induction of RORγt in these cells. At later stages, CNS9 plays a critical role, particularly in the development of RORγt⁺ APCs, contributing to colonic pTreg induction. This hierarchical transcriptional regulation is essential for SLO formation, postnatal type 3 immunity, and restraining excessive intestinal type 2 immune responses through pTreg induction.

ORGANISM(S): Mus musculus

PROVIDER: GSE311597 | GEO | 2026/01/26

REPOSITORIES: GEO

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A hierarchical Rorc(γt) cis-regulatory cascade orchestrates differentiation of RORγt⁺ innate immune cells [ChIL-seq]

Project description:Beyond its well-established role in type 3 immunity, RORγt+ innate immune cells are also essential for secondary lymphoid organ (SLO) formation and gut homeostasis. However, the transcriptional regulatory mechanisms governing RORγt expression in these cells, including ILC3s, LTi cells, and antigen-presenting cells (APCs), remain largely unknown. Here, we identify two key cis-regulatory elements within conserved non-coding sequences (CNS) 9 and 11 in the Rorc locus, which are sequentially utilized during their differentiation. Initially, Runx-binding sites in CNS11 establish chromatin accessibility as early as the HSC stage. Notably, disruption of this chromatin priming prevents subsequent transcriptional activation, thereby abolishing the initial induction of RORγt in these cells. At later stages, CNS9 plays a critical role, particularly in the development of RORγt⁺ APCs, contributing to colonic pTreg induction. This hierarchical transcriptional regulation is essential for SLO formation, postnatal type 3 immunity, and restraining excessive intestinal type 2 immune responses through pTreg induction.

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A hierarchical Rorc(γt) cis-regulatory cascade orchestrates differentiation of RORγt⁺ innate immune cells [ATAC-seq]

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A cis-element at the Rorc locus regulates the development of type 3 innate lymphoid cells

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2023-02-28 | GSE225928 | GEO

Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens

Project description:The intestinal immune system maintains tolerance to harmless food proteins and gut microbiota through peripherally-derived RORγt+Tregs (pTregs), which prevent food intolerance and inflammatory bowel disease. Recent studies suggested that RORγt+ antigen-presenting cells (APCs), which encompass rare dendritic cell (DC) subsets and type 3 innate lymphoid cells (ILC3s), are key to pTregs induction. Here, we developed a mouse with reduced RORγt+APCs by deleting a specific cis-regulatory element of Rorc encoding RORγt. Single-cell RNA-sequencing and flow cytometry analyses confirmed the depletion of a RORγt+DC subset and ILC3s. These mice showed a secondary reduction in pTregs, impaired tolerance to oral antigens and increase in Th2 cells. Conversely, newly and previously generated ILC3-deficient mice showed no pTregs or Th2 cells abnormalities. Lineage tracing revealed that RORγt+DCs share a lymphoid origin with ILC3s, consistent with their similar phenotypic traits. These findings highlight a unique role of lymphoid RORγt+DCs in maintaining intestinal immune balance and preventing conditions like food allergies.

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Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens

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Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens

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Classical dendritic cells are required for dietary antigen-mediated peripheral regulatory T cell and tolerance induction I

Project description:Oral tolerance prevents pathological inflammatory responses towards innocuous foreign antigens via peripheral regulatory T cells (pTreg cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure to instruct naÃ¯ve CD4+ T cells to differentiate into pTreg cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs are dispensable, while classical dendritic cells (cDCs) are critical for pTreg cell induction and oral tolerance. CD11bÂ¬â cDCs from the gut-draining lymph nodes efficiently induced pTreg cells, and conversely, loss of IRF8-dependent CD11bâ cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in pTreg cell induction and their redundancy during oral tolerance development. Four dendritic cell subpopulations from mouse mesenteric lymphnodes were sorted and compared in their gene expression profile

2016-03-28 | E-GEOD-77303 | biostudies-arrayexpress

Gene Expression profile of RORγt-lineage anitigen presenting cells collected from secondary lymphoid tissues in adult mice.

Project description:A key feature of immune tolerance is the ability to distinguish pathogens from innocuous signals including dietary antigens, but the precise mechanisms of oral tolerance induction and the key cellular actors have remained unclear. Classical dendritic cells (cDCs) have previously been implicated in the generation of regulatory T cells (Tregs) and T-cell anergy in response to food antigens in gut-associated lymphoid tissue1, but here we demonstrate that RORγt-lineage antigen-presenting cells (APCs), specifically RORγt-lineage cells expressing the Autoimmune Regulator (Aire) gene – referred to as RORγt eTACs – are the critical APC population required for oral tolerance induction. We reconcile the identity of these rare RORγt-lineage APC populations across new and all known single-cell transcriptomic datasets to establish consensus identities and show that RORγt eTACs2 are a unique myeloid-derived lineage distinct from innate lymphoid cells (ILCs) which are both necessary and sufficient for oral tolerance induction.

2025-04-15 | GSE273746 | GEO

Classical dendritic cells are required for dietary antigen-mediated peripheral regulatory T cell and tolerance induction II

Project description:Oral tolerance prevents pathological inflammatory responses towards innocuous foreign antigens via peripheral regulatory T cells (pTreg cells). However, whether a particular subset of antigen-presenting cells (APCs) is required during dietary antigen exposure to instruct naÃ¯ve CD4+ T cells to differentiate into pTreg cells has not been defined. Using myeloid lineage-specific APC depletion in mice, we found that monocyte-derived APCs are dispensable, while classical dendritic cells (cDCs) are critical for pTreg cell induction and oral tolerance. CD11bÂ¬â?? cDCs from the gut-draining lymph nodes efficiently induced pTreg cells, and conversely, loss of IRF8-dependent CD11bâ?? cDCs impaired their polarization, although oral tolerance remained intact. These data reveal the hierarchy of cDC subsets in pTreg cell induction and their redundancy during oral tolerance development. Sorted naÃ¯ve CD45.1 OT-II CD4 T cells were co-cultured with four dendritic cell subpopulations sorted from mouse mesenteric lymphnodes. 24h later OT-II cells were sorted again and compared in their gene expression profile.

2016-03-28 | E-GEOD-77304 | biostudies-arrayexpress

DOCK8 regulates protective immunity by controlling the function and survival of RORγt+ ILCs

Project description:Retinoic-acid receptor-related orphan receptor-γt-positive (RORγt+) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt+ ILCs is not thoroughly understood. Here we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt+ ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt+ ILCs are less responsive to IL-7 mediated signaling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt+ ILCs. Control and DOCK8 KO mice were infected with 2X109 CFU of Citrobacter rodentium and day 8 post infection mice were sacrificed and their colons were harvested (n=5) . Total RNA was purified from the infected colons with RNeasy mini kit (Qiagen). RNA sequencing was performed (pooled RNA sample from five mice in each group) at Genomic Core Facility Southwestern Medical Center, University of Texas.

2014-06-25 | E-GEOD-58765 | biostudies-arrayexpress

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