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

TitleNovel antigen presenting cell imparts Treg-dependent tolerance to gut microbiota.
Publication TypeJournal Article
Year of Publication2022
AuthorsAkagbosu B, Tayyebi Z, Shibu G, Iza YAPaucar, Deep D, Parisotto YFranco, Fisher L, H Pasolli A, Thevin V, Elmentaite R, Knott M, Hemmers S, Jahn L, Friedrich C, Verter J, Wang Z-M, van den Brink M, Gasteiger G, Grünewald TGP, Marie JC, Leslie C, Rudensky AY, Brown CC
JournalNature
Date Published2022 Sep 07
ISSN1476-4687
Abstract

Establishing and maintaining tolerance to self- or innocuous foreign antigens is vital for preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing AutoImmune Regulator, Aire, play 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 dietary and commensal microbiota derived antigens5-8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells are not known. Here we identified a new class of RORγt+ antigen-presenting cells (APC), dubbed Thetis cells (TCs), with transcriptional features of both mTECs and dendritic cells (DCs), comprising 4 major sub-groups (TC I-IV). We uncovered a developmental wave of TCs within intestinal lymph nodes during a critical early life window, coincident with the wave of pTreg cell differentiation. While TC I and III expressed the signature mTEC nuclear factor Aire, TC IV lacked Aire expression and were enriched for molecules required for pTreg generation, including the TGF-β activating integrin αvβ8. Loss of either MHCII or Itgb8 expression by TCs led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. In contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical DCs was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ APC with an essential early life function. Our studies reveal parallel pathways for establishment of tolerance to self and foreign antigen within the thymus and periphery, respectively, marked by involvement of shared cellular and transcriptional programs.

DOI10.1038/s41586-022-05309-5
Alternate JournalNature
PubMed ID36070798

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