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

Author:

Rodrigues, Patrick Fernandes

Wu, Shitong

Trsan, Tihana

Panda, Santosh K

Fachi, José Luís

Liu, Yizhou

Du, Siling

de Oliveira, Sarah

Antonova, Alina Ulezko

Khantakova, Darya

Sudan, Raki

Desai, Pritesh

Diamond, Michael S

Gilfillan, Susan

Anderson,Stephen

Cella, Marina

Colonna, Marco
Author Address

Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA., Department of Genetics and Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil., Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA., Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA; Department of Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA., Basic Science Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA., Department of Pathology and Immunology, Washington University School of Medicine in Saint Louis, Saint Louis, MO, USA. Electronic address: mcolonna@wustl.edu.,

Abstract:

The intestinal immune system maintains tolerance to harmless food proteins and gut microbiota through peripherally derived ROR gamma t+ Tregs (pTregs), which prevent food intolerance and inflammatory bowel disease. Recent studies suggested that ROR gamma t+ antigen-presenting cells (APCs), which encompass rare dendritic cell (DC) subsets and type 3 innate lymphoid cells (ILC3s), are key to pTreg induction. Here, we developed a mouse with reduced ROR gamma t+ APCs by deleting a specific cis-regulatory element of Rorc encoding ROR gamma t. Single-cell RNA sequencing and flow cytometry analyses confirmed the depletion of a ROR gamma t+ DC subset and ILC3s. These mice showed a secondary reduction in pTregs, impaired tolerance to oral antigens, and an increase in T helper (Th)2 cells. Conversely, ILC3-deficient mice showed no pTregs or Th2 cell abnormalities. Lineage tracing revealed that ROR gamma t+ DCs share a lymphoid origin with ILC3s, consistent with their similar phenotypic traits. These findings highlight the role of lymphoid ROR gamma t+ DCs in maintaining intestinal immune balance and preventing conditions like food allergies. Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.

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