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Akagbosu, Blossom; Tayyebi, Zakieh; Shibu, Gayathri; Iza, Yoselin A. Paucar; Deep, Deeksha; Parisotto, Yollanda Franco; Fisher, Logan; Pasolli, H. Amalia; Thevin, Valentin; Elmentaite, Rasa; Knott, Maximilian; Hemmers, Saskia; Jahn, Lorenz; Friedrich, Christin; Verter, Jacob; Wang, Zhong-Min; Brink, Marcel van den; Gasteiger, Georg; Gruenewald, Thomas G. P.; Marie, Julien C.; Leslie, Christina; Rudensky, Alexander Y. and Brown, Chrysothemis C. (2022): Novel antigen-presenting cell imparts T-reg-dependent tolerance to gut microbiota. In: Nature, Vol. 610, No. 7933: pp. 752-760

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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 (T-reg) cell development(1-4). Within weeks of birth, a separate wave of T-reg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota(5-8), yet the cell types responsible for the generation of peripheral T-reg (pT(reg)) cells have not been identified. Here we describe the identification of a class of ROR gamma t(+) 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 pT(reg) 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 pT(reg) generation, including the TGF-beta-activating integrin alpha v beta 8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pT(reg) differentiation, with ensuing colitis. By contrast, MHCII expression by ROR gamma t(+) group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pT(reg) generation, further implicating TC IV as the tolerogenic ROR gamma t(+) 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.

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