RORγt eTACs mediate oral tolerance and Treg induction

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

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Publication Details

Journal
The Journal of Experimental Medicine
Published
2025-04-29
DOI
https://doi.org/10.1084/jem.20250573
Citations
28
Primary Topic
IL-33, ST2, and ILC Pathways
Type
article
Field-Weighted Citation Impact
22.33

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article

RORγt eTACs mediate oral tolerance and Treg induction

Matthew P. Arvedson, Vasilis Ntranos, Im‐Hong Sun, James M. Gardner et al.
28 citations
The Journal of Experimental Medicine
IL-33, ST2, and ILC Pathways
22.33
article

RORγt eTACs mediate oral tolerance and Treg induction

Matthew P. Arvedson, Vasilis Ntranos, Im‐Hong Sun, James M. Gardner, Richard M. Locksley, Martín Valdearcos, Roberto R. Ricardo-González, Anita Qualls, Joe Germino, Jiaxi Wang, Sheng Zhong, Juan Du, Han Yin, Nolan K. Horner
article en
28 citations

Abstract

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

The Journal of Experimental MedicineVol. 222(8)
Howard Hughes Medical Institute (US), University of California, San Francisco (US)
Burroughs Wellcome Fund, W. M. Keck Foundation, Achievement Rewards for College Scientists Foundation, Parker Institute for Cancer Immunotherapy, National Institutes of Health
Zero hunger
Openalex Percentile: Top 0%
IL-33, ST2, and ILC Pathways
22.33
DOISourceOpenAlex
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