GILT-mediated processing of a self and melanoma antigen in thymic epithelial cells promotes deletion and regulatory T cells (APP3P.113)

Abstract

Abstract Central tolerance is critical to prevent autoimmunity, but limits T cell responses to tumor Ag that are self Ag. We have identified that gamma-interferon-inducible lysosomal thiol reductase (GILT) is required for thymic deletion of CD4+ T cells specific for the 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 MHC class II-restricted presentation of endogenous TRP1 by pooled thymic APC. Bone marrow (BM) chimeras demonstrate that GILT expression in TEC is necessary and sufficient for efficient deletion of TRP1-specific thymocytes. In chimeras that express GILT in TEC, TRP1-specific T cells undergo deletion, and chimeras are not protected from melanoma challenge. Although an intermediate level of TRP1-specific T cells develop in chimeras with GILT expression limited to BM-derived cells, only chimeras lacking GILT in both populations are protected from melanoma challenge. Chimeras that express GILT in TECs or in which GILT is limited to BM-derived cells have a substantially higher percentage of TRP1-specific regulatory T (Treg) cells and lower effector:Treg cell ratio. These findings suggest that GILT operates in mTEC to facilitate the presentation of tissue-specific self Ag and promote deletion and development of Treg cells.