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

Cell, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

The intestinal immune system maintains tolerance to harmless food proteins and gut microbiota through peripherally derived RORγt+ Tregs (pTregs), which prevent intolerance inflammatory bowel disease. Recent studies suggested that antigen-presenting cells (APCs), encompass rare dendritic cell (DC) subsets type 3 innate lymphoid (ILC3s), are key pTreg induction. Here, we developed a mouse with reduced APCs by deleting specific cis-regulatory element of Rorc encoding RORγt. Single-cell RNA sequencing flow cytometry analyses confirmed the depletion DC subset ILC3s. These mice showed secondary reduction in pTregs, impaired oral antigens, an increase T helper (Th)2 cells. Conversely, ILC3-deficient no pTregs or Th2 abnormalities. Lineage tracing revealed DCs share origin ILC3s, consistent their similar phenotypic traits. findings highlight role maintaining balance preventing conditions like allergies.

Язык: Английский

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RORγt eTACs mediate oral tolerance and Treg induction

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(8)

Опубликована: Апрель 15, 2025

The immune system must distinguish pathogens from innocuous dietary antigens, but the precise mechanisms and cellular actors remain unclear. Here, we demonstrate that RORγt-lineage APCs are required for oral tolerance. Using lineage tracing single-cell sequencing, show these consist of three principal populations: type 3 innate lymphoid cells (ILC3s), dendritic cells, expressing Aire called RORγt eTACs (R-eTACs)-also known as Janus or Thetis cells. We R-eTACs, not ILC3s, tolerance induction. find R-eTACs probable myeloid origin uniquely express integrin β8 (Itgb8). Both MHCII Itgb8 expression in necessary to induce food-specific regulatory T Mice lacking with deletion fail generate Tregs instead develop a T-follicular helper response elevated antigen-specific antibodies. These findings establish critical mediators suggest novel targets modulate

Язык: Английский

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RORγt-dependent antigen-presenting cells direct regulatory T cell-mediated tolerance to food antigen

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 24, 2024

Abstract The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microbes with potential induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses these agents 1–4 . While RORγt + antigen-presenting (RORγt-APCs) were shown program gut microbiota-specific pTreg 5–7 , their definition remains incomplete, the APC responsible tolerance has remained elusive. Here, we identify a distinct subset of RORγt-APCs, designated tolerogenic dendritic (tDC), required differentiation both food- establishment oral tolerance. tDC development function require expression transcription factors Prdm16 RORγt, as well unique Rorc(t) cis-regulatory element. Gene expression, chromatin accessibility, surface marker analysis establish myeloid origin, from ILC3, sharing epigenetic profiles classical DC. Upon genetic perturbation tDC, observe substantial increase antigen-specific helper 2 (Th2) lieu pTreg, leading compromised mouse models asthma allergy. Single-cell analyses freshly resected mesenteric lymph nodes human organ donor, multiple specimens intestine tonsil, reveal candidate co-expression PRDM16 RORC an extensive transcriptome shared mice, highlighting evolutionarily conserved role across species. Our findings suggest that better understanding how develop they regulate cell microbial could offer new insights into developing therapeutic strategies autoimmune allergic diseases transplant

Язык: Английский

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“What’s in a name?” Clarifying the identity of RORγt+ antigen-presenting cells

The Journal of Experimental Medicine, Год журнала: 2025, Номер 222(8)

Опубликована: Май 15, 2025

Recent publications have demonstrated that antigen-presenting cells (APCs) targeted by Rorc-cre (also known as RORγt-cre) are required for the induction of peripheral regulatory T (pTreg) in response to commensal and dietary antigens. In this issue JEM, Sun et al. (https://doi.org/10.1084/jem.20250573) provide key insights into identity these cells, revealing Rorc-cre–traced APCs include group 3 innate lymphoid (ILC3s), dendritic (DCs), extrathymic AIRE-expressing (eTACs). Their work highlights eTACs critical inducing RORγt+ pTregs specific food antigens, while implicating DCs generation RORγt− pTregs.

Язык: Английский

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Thetis cells: regulators of intestinal immune tolerance

Current Opinion in Immunology, Год журнала: 2025, Номер 95, С. 102570 - 102570

Опубликована: Май 26, 2025

Язык: Английский

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