Prdm16-dependent Antigen-presenting Cells Induce Tolerance to Intestinal Antigens

Overview

Journal bioRxiv

Date 2024 Aug 2

PMID 39091750

Authors

Liuhui Fu

Rabi Upadhyay

Maria Pokrovskii

Francis M Chen

Gabriela Romero-Meza

Adam Griesemer

Dan R Littman

Affiliations

Soon will be listed here.

Abstract

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

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