GILT expression in medullary thymic epithelial cells is required for presentation of tissue-specific self antigens and deletion of autoreactive T cells (P5037)

Abstract

Abstract Clonal deletion of thymocytes with high avidity for self-peptide:MHC complexes is critical for the maintenance of tolerance and prevention of autoimmunity. We have shown that gamma-interferon-inducible lysosomal thiol reductase (GILT) is required for thymic deletion of T cells specific for a self and melanoma Ag, tyrosinase-related protein 1 (TRP1). To define GILT’s role in central tolerance, we show that GILT expression is enriched in thymic APC capable of mediating deletion, medullary thymic epithelial cells (mTEC) and dendritic cells. TRP1 expression is restricted to mTEC. GILT facilitates the MHC class II-restricted presentation of endogenous TRP1 by pooled thymic APC (TEC and bone marrow (BM)-derived APC). Using BM chimeras, we show that TRP1-specific T cells are deleted in chimeras in which GILT is expressed in both TEC and BM-derived APC or GILT expression is restricted to TEC, indicating that GILT expression in TEC is sufficient for deletion of TRP1-specific thymocytes. In contrast, a large number of TRP1-specific T cells develop in chimeras which lack GILT expression in both TEC and BM-derived APC. Chimeras in which GILT expression is limited to BM-derived APC have intermediate levels of TRP1-specific T cells, demonstrating that GILT expression in TEC is required for efficient deletion of TRP1-specific thymocytes. These findings suggest that GILT operates in mTEC to facilitate the presentation of tissue-specific self Ag and promote deletion of autoreactive T cells.