GILT in Thymic Epithelial Cells Facilitates Central CD4 T Cell Tolerance to a Tissue-Restricted, Melanoma-Associated Self-Antigen

• DOI: 10.4049/jimmunol.1900523
• Publication Date: 2020-04-08T21:05:42Z
• Authors: Matthew P Rausch; Lydia R Meador; Todd C Metzger; Handong Li; Shenfeng Qiu; Mark S Anderson; K Taraszka Hastings
• Keywords: Central tolerance; Negative selection

Central tolerance prevents autoimmunity, but also limits T cell responses to potentially immunodominant tumor epitopes with limited expression in healthy tissues. In peripheral APCs, γ-IFN-inducible lysosomal thiol reductase (GILT) is critical for MHC class II-restricted presentation of disulfide bond-containing proteins, including the self-antigen and melanoma Ag tyrosinase-related protein 1 (TRP1). The role GILT thymic processing generation central has not been investigated. We found that enhanced negative selection TRP1-specific thymocytes mice. was enriched APCs capable mediating deletion, namely medullary epithelial cells (mTECs) dendritic cells, whereas TRP1 restricted solely mTECs. facilitated endogenous by pooled APCs. Using bone marrow chimeras, (TECs), hematopoietic sufficient complete deletion thymocytes. An increased frequency regulatory (Treg) present chimeras Only lacked both TECs had a high conventional T/Treg ratio were protected from challenge. Thus, mTECs particular, preferentially facilitates presentation, selection, Treg resulting diminished antitumor response tissue-restricted, melanoma-associated self-antigen.