Author
Listed:
- Blossom Akagbosu
(Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center)
- Zakieh Tayyebi
(Memorial Sloan Kettering Cancer Center
Weill Cornell Graduate School)
- Gayathri Shibu
(Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Weill Cornell Medicine Graduate School of Medical Sciences)
- Yoselin A. Paucar Iza
(Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Weill Cornell Medicine Graduate School of Medical Sciences)
- Deeksha Deep
(Weill Cornell Medicine Graduate School of Medical Sciences
Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center
Weill Cornell Medicine, The Rockefeller University and Memorial Sloan Kettering Cancer Center)
- 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
Weill Cornell Medicine Graduate School of Medical Sciences)
- H. Amalia Pasolli
(The Rockefeller University)
- Valentin Thevin
(CRCL, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université de Lyon
Equipe Labellisée Ligue Nationale contre le Cancer)
- Rasa Elmentaite
(Wellcome Sanger Institute)
- Maximilian Knott
(LMU Munich)
- Saskia Hemmers
(Weill Cornell Medicine Graduate School of Medical Sciences
Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center
Duke University)
- 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
Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center)
- Georg Gasteiger
(Julius-Maximilians-Universität Würzburg)
- Thomas G. P. Grünewald
(Hopp—Children’s Cancer Center Heidelberg (KiTZ)
German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK)
Heidelberg University Hospital)
- Julien C. Marie
(CRCL, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université de Lyon
Equipe Labellisée Ligue Nationale contre le Cancer)
- Christina Leslie
(Memorial Sloan Kettering Cancer Center)
- Alexander Y. Rudensky
(Weill Cornell Medicine Graduate School of Medical Sciences
Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center)
- Chrysothemis C. Brown
(Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center
Weill Cornell Medicine Graduate School of Medical Sciences
Memorial Sloan Kettering Cancer Center
Memorial Sloan Kettering Cancer Center)
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.
Suggested Citation
Blossom Akagbosu & Zakieh Tayyebi & Gayathri Shibu & Yoselin A. Paucar Iza & Deeksha Deep & Yollanda Franco Parisotto & Logan Fisher & H. Amalia Pasolli & Valentin Thevin & Rasa Elmentaite & Maximilia, 2022.
"Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota,"
Nature, Nature, vol. 610(7933), pages 752-760, October.
Handle:
RePEc:nat:nature:v:610:y:2022:i:7933:d:10.1038_s41586-022-05309-5
DOI: 10.1038/s41586-022-05309-5
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Cited by:
- Anna-Lena Geiselhöringer & Daphne Kolland & Arisha Johanna Patt & Linda Hammann & Amelie Köhler & Luisa Kreft & Nina Wichmann & Miriam Hils & Christiane Ruedl & Marc Riemann & Tilo Biedermann & David , 2024.
"Dominant immune tolerance in the intestinal tract imposed by RelB-dependent migratory dendritic cells regulates protective type 2 immunity,"
Nature Communications, Nature, vol. 15(1), pages 1-17, December.
- Adélaïde Gélineau & Geneviève Marcelin & Melissa Ouhachi & Sébastien Dussaud & Lise Voland & Raoul Manuel & Ines Baba & Christine Rouault & Laurent Yvan-Charvet & Karine Clément & Roxane Tussiwand & T, 2024.
"Fructooligosaccharides benefits on glucose homeostasis upon high-fat diet feeding require type 2 conventional dendritic cells,"
Nature Communications, Nature, vol. 15(1), pages 1-13, December.
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