GILT in thymic epithelial cells preferentially facilitates MHC class II-restricted presentation in generating central T cell tolerance to a self and melanoma antigen

Abstract

Abstract Central tolerance prevents autoimmunity, but limits T cell responses to tumor antigens that are self antigens. In peripheral APCs, gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of disulfide bond-containing proteins, including the self and melanoma antigen tyrosinase-related protein 1 (TRP1). The role of GILT in thymic antigen processing and generation of central tolerance is unknown. We found that GILT enhanced the clonal deletion of TRP1-specific thymocytes. GILT expression was enriched in thymic APCs capable of mediating deletion, namely medullary thymic epithelial cells (mTECs) and dendritic cells. TRP1 expression was restricted to mTECs. GILT facilitated MHC class II-restricted presentation of endogenous TRP1 by pooled thymic APCs. Using bone marrow chimeras, GILT expression in thymic epithelial cells (TECs), but not hematopoietic cells, was sufficient for deletion of TRP1-specific thymocytes. Chimeras with GILT expression in TECs also had an increased frequency of TRP1-specific regulatory T (Treg) cells. These data demonstrate an advantage of TEC-derived GILT for antigen processing and subsequent T cell tolerance. Only chimeras that lacked GILT in both TECs and hematopoietic cells were protected from melanoma and had a high effector T cell:Treg cell ratio. Thus, GILT diminishes T cell-mediated protection from melanoma through promoting thymic deletion and Treg cells.