Functionally diverse thymic medullary epithelial cells interplay to direct central tolerance

Author:

Ushio, Aya

Matsuda-Lennikov, Mami

Kalle-Youngoue,Felix

Shimizu, Akihide

Abdelmaksoud, Abdalla

Kelly, Michael C

Ishimaru, Naozumi

Takahama, Yousuke
Author Address

Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Oral Molecular Pathology, Graduate School of Biomedical Sciences, Tokushima University, Kuramoto, Tokushima 770-8504, Japan., Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21701, USA., Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Single Cell Analysis Facility, Cancer Research Technology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: yousuke.takahama@nih.gov.,

Abstract:

Medullary thymic epithelial cells (mTECs) are essential for the establishment of self-tolerance in T cells. Promiscuous gene expression by a subpopulation of mTECs regulated by the nuclear protein Aire contributes to the display of self-genomic products to newly generated T cells. Recent reports have highlighted additional self-antigen-displaying mTEC subpopulations, namely Fezf2-expressing mTECs and a mosaic of self-mimetic mTECs including thymic tuft cells. In addition, a functionally different subset of mTECs produces chemokine CCL21, which attracts developing thymocytes to the medullary region. Here, we report that CCL21+ mTECs and Aire+ mTECs non-redundantly cooperate to direct self-tolerance to prevent autoimmune pathology by optimizing the deletion of self-reactive T cells and the generation of regulatory T cells. We also detect cooperation for self-tolerance between Aire and Fezf2, the latter of which unexpectedly regulates thymic tuft cells. Our results indicate an indispensable interplay among functionally diverse mTECs for the establishment of central self-tolerance. Published by Elsevier Inc.

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