title: Medullary thymic epithelial cells and CD8α+dendritic cells coordinately regulate central tolerance but CD8α+cells are dispensable for thymic regulatory T cell production.
abstract: In the thymus, antigen presenting cells (APCs) namely, medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) regulate T cell tolerance through elimination of autoreactive T cells and production of thymic T regulatory (tTreg) cells. How the different APCs in the thymus share the burden of tolerazing the emerging T cell repertoire remains unclear. For example, while mutations that inhibit mTEC development or function associate with peripheral autoimmunity, the role of tDCs in organ-specific autoimmunity and tTreg cell production remains controversial. In this report we used mice depleted of mTECs and/or CD8α+DCs, to examine the contributions of these cell populations in thymic tolerance. We found that while mice depleted of CD8α+DCs or mTECs were normal or developed liver inflammation respectively, combined depletion of mTECs and CD8α+DCs resulted in overt peripheral autoimmunity. The autoimmune manifestations in mice depleted of both mTECs and CD8α+cDCs associated with increased percentages of CD4+and CD8+T cells in the thymus. In contrast, while mTEC depletion resulted in reduced percentages of tTreg cells, no additional effect was observed when CD8α+DCs were also depleted. These results reveal that: 1) mTECs and CD8α+DCs cooperatively safeguard against peripheral autoimmunity through thymic T cell deletion; 2) CD8α+DCs are dispensable for tTreg cell production, whereas mTECs play a non-redundant role in this process; 3) mTECs and CD8α+DCs make unique contributions to tolerance induction that cannot be compensated for by other thymic APCs such as migratory SIRPα+or plasmacytoid DCs.
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Herbin
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Bonito
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Seihwan
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Erica G
authors.initials: EG
authors.lastname: Weinstein
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute/Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Adeeb H
authors.initials: AH
authors.lastname: Rahman
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute/Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Merad
authors.affiliation: Department of Medicine/Clinical Immunology, The Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: k.alexandropoulos@mssm.edu.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Alexandropoulos
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology* / Q000378:metabolism; D061167:Central Tolerance / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology; D008212:Lymphocyte Depletion; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018448:Models, Immunological; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic
keywords: Autoimmunity; Dendritic cells; Medullary thymic epithelial cells; Regulatory T cells