Claudin 1-mediated positioning of DC1 to mTECs is essential for antigen transfer-coupled DC1 maturation and maintenance of central tolerance

Abstract

The mechanisms of central tolerance, which rely on the presentation of self-antigens by medullary thymic epithelial cells (mTECs) and DCs, prevent autoimmunity by eliminating self-reactive T-cells. While mTECs produce self-antigens in an autonomous manner, DCs acquire them from mTECs via cooperative antigen transfer (CAT). Our recent data showed that preferential pairing occurs between distinct subsets of mTECs and DCs in CAT, providing a rationale for the existence of molecular determinants which control such pairing and the outcome of central tolerance. Here, we compared the transcriptomes of CAT-experienced and -inexperienced DCs and identified Claudin 1 as a molecule involved in CAT-coupled type 1 DC (DC1) maturation. By mapping thymic DC1 heterogeneity, we identified their early and late maturation states. DC1-specific ablation of Claudin 1 led to a reduction in CAT-experienced late mature DC1s and hampered DC1 maturation. These phenotypes correlated with the displacement of DC1s from the vicinity of mTECs. This translated into impaired Treg selection and clonal deletion of TRA-specific T-cells manifested via a break in tolerance and symptoms of multi-organ autoimmunity. Collectively, our results identify thymic DC1-derived Claudin 1 as a regulator of immune tolerance. One Sentence SummaryThe expression of Claudin 1 on type 1 dendritic cells regulates their proximity to mTECs, which is required for effective antigen transfer coupled with DC1 maturation and establishment of T-cell tolerance.