TRP1 Peptide Requires Internalization and is Partially Dependent on GILT for Efficient Presentation on MHC Class II

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.Tyrosinase-related protein 1 (TRP1) is a melanosomal integral membrane protein and melanocyte differentiation antigen that contributes to the synthesis of melanin in melanocytes. Present in both benign and malignant melanocytes, it has been implicated in the autoimmune development of vitiligo and melanoma antitumor immunity. Since a naturally occurring MHC class II-restricted TRP1 epitope contains cysteine residues, we hypothesized that this epitope will require internalization and reduction by gamma-interferon-inducible lysosomal thiol reductase (GILT) for presentation on class II. GILT is known to catalyze the reduction of protein disulfide bonds in the endocytic pathway and contribute to antigen processing and presentation of certain MHC class I and class II epitopes. We have previously shown that GILT is required for efficient class II-restricted presentation of TRP1. Here, we found that TRP1 peptide presentation is partially dependent on GILT and that TRP1 peptide requires internalization for efficient presentation on class II. We also determined that antigen presentation increased with increasing peptide dose and increasing APC:T cell ratio. Compared to other TRP1-specific T cells, primary TRP1-specific T cells from TRP1BwRAG-/- 5 TRP1tg mice produce maximal IL-2 in response to presentation of TRP1. These results further illustrate the importance of GILT in the processing and presentation of TRP1. Thus, GILT may play a role in both the development of autoimmune vitiligo and anti-melanoma immune responses.This item is part of the College of Medicine - Phoenix Scholarly Projects 2012 collection. For more information, contact the Phoenix Biomedical Campus Library at pbc-library@email.arizona.edu