RORγt eTACs mediate oral tolerance and Treg induction

Im-Hong Sun^#^{1

2}, Anita E Qualls^#², Han S Yin^#², Jiaxi Wang^#², Matthew P Arvedson², Joe Germino², Nolan K Horner^{1

2}, Sheng Zhong^{1

2}, Juan Du^{1

2}, Martin Valdearcos², Vasilis Ntranos^{2

3}, Richard M Locksley^{4

5

6}, Roberto R Ricardo-Gonzalez⁷, James M Gardner^{1

2}

Affiliations

¹ Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
² Diabetes Center, University of California, San Francisco , San Francisco, CA, USA.
³ Department of Epidemiology and Biostatistics, Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁶ University of California, Howard Hughes Medical Institute, San Francisco , San Francisco, CA, USA.
⁷ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.

^# Contributed equally.

PMID: 40298935
PMCID: PMC12039581 (available on 2026-04-29)
DOI: 10.1084/jem.20250573

RORγt eTACs mediate oral tolerance and Treg induction

Im-Hong Sun et al. J Exp Med. 2025.

. 2025 Aug 4;222(8):e20250573.

doi: 10.1084/jem.20250573. Epub 2025 Apr 29.

Authors

Affiliations

¹ Department of Surgery, University of California, San Francisco, San Francisco, CA, USA.
² Diabetes Center, University of California, San Francisco , San Francisco, CA, USA.
³ Department of Epidemiology and Biostatistics, Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA.
⁴ Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
⁵ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA, USA.
⁶ University of California, Howard Hughes Medical Institute, San Francisco , San Francisco, CA, USA.
⁷ Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA.

^# Contributed equally.

PMID: 40298935
PMCID: PMC12039581 (available on 2026-04-29)
DOI: 10.1084/jem.20250573

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.

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Conflict of interest statement

Disclosures: R.M. Locksley reported other from Genentech outside the submitted work. No other disclosures were reported.

References

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RORγt eTACs mediate oral tolerance and Treg induction

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RORγt eTACs mediate oral tolerance and Treg induction

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