Functionally diverse thymic medullary epithelial cells interplay to direct central tolerance
Aya Ushio,
Mami Matsuda-Lennikov,
Felix Kalle-Youngoue,
Akihide Shimizu,
Abdalla Abdelmaksoud,
Michael C. Kelly,
Naozumi Ishimaru,
Yousuke Takahama
Affiliations
Aya Ushio
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
Mami Matsuda-Lennikov
Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Felix Kalle-Youngoue
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
Akihide Shimizu
Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Abdalla Abdelmaksoud
Center for Cancer Research Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Michael C. Kelly
Single Cell Analysis Facility, Cancer Research Technology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
Naozumi Ishimaru
Department of Oral Molecular Pathology, Graduate School of Biomedical Sciences, Tokushima University, Kuramoto, Tokushima 770-8504, Japan
Yousuke Takahama
Thymus Biology Section, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Corresponding author
Summary: 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.
