Central tolerance, which relies on the presentation of self-antigens by mTECs and DCs, prevents autoimmunity by eliminating self-reactive T cells. While mTECs produce self-antigens autonomously, DCs acquire them from mTECs via cooperative antigen transfer (CAT). We previously showed that mTEC and DC subsets exhibit preferential pairing in CAT, providing a rationale for the existence of molecular determinants underpinning this pairing and its outcome. Here, we compared the transcriptomes of CAT-experienced and CAT-inexperienced DCs and identified Claudin 1 as a molecule involved in CAT and type 1 DC (DC1) maturation. DC1-specific ablation of Claudin 1 resulted in decreased CAT to late mature DC1s and dramatically diminished DC1 maturation. These phenotypes correlated with the displacement of DC1s from mTECs and their decreased expression of MHCII pathway genes. This translated into impaired Treg selection and clonal deletion, ultimately manifesting in symptoms of multiorgan autoimmunity and shortened lifespan. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance.

Advanced Comprehensive Research Organization Teikyo University Tokyo Japan

Centre d'Immunologie de Marseille Luminy Aix Marseille Universite´ Inserm CNRS Marseille France

Czech Centre of Phenogenomics and Laboratory of Transgenic Models of Diseases Institute of Molecular Genetics of the Czech Academy of Sciences Vestec Czech Republic

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Institute of Immunology and Immunotherapy University of Birmingham Birmingham UK

Laboratory of Adaptive Immunity Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Genomics and Bioinformatics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Laboratory of Immunobiology Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

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