Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Blossom Akagbosu, Zakieh Tayyebi, Gayathri Shibu, Yoselin A. Paucar Iza, Deeksha Deep, Yollanda Franco Parisotto, Logan Fisher, H. Amalia Pasolli, Valentin Thevin, Rasa Elmentaite, Maximilian Knott, Saskia Hemmers, Lorenz Jahn, Christin Friedrich, Jacob Verter, Zhong-Min Wang, Marcel Brink, Georg Gasteiger, Thomas G. P. Grünewald, Julien C. Marie, Christina Leslie, Alexander Y. Rudensky () and Chrysothemis C. Brown ()
Additional contact information
Blossom Akagbosu: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Zakieh Tayyebi: Memorial Sloan Kettering Cancer Center
Gayathri Shibu: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Yoselin A. Paucar Iza: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Deeksha Deep: Weill Cornell Medicine Graduate School of Medical Sciences
Yollanda Franco Parisotto: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Logan Fisher: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
H. Amalia Pasolli: The Rockefeller University
Valentin Thevin: CRCL, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université de Lyon
Rasa Elmentaite: Wellcome Sanger Institute
Maximilian Knott: LMU Munich
Saskia Hemmers: Weill Cornell Medicine Graduate School of Medical Sciences
Lorenz Jahn: Memorial Sloan Kettering Cancer Center
Christin Friedrich: Julius-Maximilians-Universität Würzburg
Jacob Verter: Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center
Zhong-Min Wang: Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center
Marcel Brink: Weill Cornell Medicine Graduate School of Medical Sciences
Georg Gasteiger: Julius-Maximilians-Universität Würzburg
Thomas G. P. Grünewald: Hopp—Children’s Cancer Center Heidelberg (KiTZ)
Julien C. Marie: CRCL, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université de Lyon
Christina Leslie: Memorial Sloan Kettering Cancer Center
Alexander Y. Rudensky: Weill Cornell Medicine Graduate School of Medical Sciences
Chrysothemis C. Brown: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center

Nature, 2022, vol. 610, issue 7933, 752-760

Abstract: Abstract Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

Date: 2022
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DOI: 10.1038/s41586-022-05309-5

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