GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development

Duan Ni; Jian Tan; Remy Robert; Jemma Taitz; Anjie Ge; Camille Potier-Villette; Julen Gabirel Araneta Reyes; Alanna Spiteri; Claire Wishart; Charles Mackay; Laura Piccio; Nicholas Jonathan Cole King; Laurence Macia

doi:10.1002/eji.202350521

GPR109A expressed on medullary thymic epithelial cells affects thymic Treg development

Eur J Immunol. 2023 Nov;53(11):e2350521. doi: 10.1002/eji.202350521. Epub 2023 Sep 7.

Authors

Duan Ni^{1

2}, Jian Tan^{1

2}, Remy Robert³, Jemma Taitz^{1

2}, Anjie Ge^{1

2}, Camille Potier-Villette^{1

2}, Julen Gabirel Araneta Reyes^{1

2}, Alanna Spiteri^{1

2

4}, Claire Wishart^{1

2

4}, Charles Mackay³, Laura Piccio^{1

2

5

6}, Nicholas Jonathan Cole King^{1

2

4}, Laurence Macia^{1

2

7}

Affiliations

¹ Charles Perkins Centre, The University of Sydney, The University of Sydney, New South Wales, Australia.
² School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
³ Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
⁴ Viral Immunopathology Laboratory, Infection, Immunity and Inflammation Research Theme, The School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
⁵ Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.
⁶ Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Sydney Cytometry, The University of Sydney and Centenary Institute, Sydney, New South Wales, Australia.

PMID: 37595951
DOI: 10.1002/eji.202350521

Abstract

Regulatory T cells (Treg) maintain immune homeostasis due to their anti-inflammatory functions. They can be generated either centrally in the thymus or in peripheral organs. Metabolites such as short-chain fatty acids produced by intestinal microbiota can induce peripheral Treg differentiation, by activating G-protein-coupled-receptors like GPR109A. In this study, we identified a novel role for GPR109A in thymic Treg development. We found that Gpr109a^-/- mice had increased Treg under basal conditions in multiple organs compared with WT mice. GPR109A was not expressed on T cells but on medullary thymic epithelial cells (mTECs), as revealed by single-cell RNA sequencing in both mice and humans and confirmed by flow cytometry in mice. mTECs isolated from Gpr109a^-/- mice had higher expression of autoimmune regulator (AIRE), the key regulator of Treg development, while the subset of mTECs that did not express Gpr109a in the WT displayed increased Aire expression and also enhanced signaling related to mTEC functionality. Increased thymic Treg in Gpr109a^-/- mice was associated with protection from experimental autoimmune encephalomyelitis, with ameliorated clinical signs and reduced inflammation. This work identifies a novel role for GPR109A and possibly the gut microbiota, on thymic Treg development via its regulation of mTECs.

Keywords: Experimental autoimmune encephalomyelitis; GPR109A; Regulatory T cell; Thymic medullary epithelial cell; Treg development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation
Epithelial Cells*
Flow Cytometry
Humans
Mice
Mice, Inbred C57BL
Signal Transduction
T-Lymphocytes, Regulatory*
Thymus Gland

Substances

Hcar2 protein, mouse