Identification of a gamma IFN inducible lysosomal thiol reductase (GILT)-dependent MHC-II associated epitope that induces T cell responses in GILT−/− mice

Autor: Xiao He, Eduardo Reyes-Vargas, Dai Hu, Xiaomin Wang, Peter E. Jensen
Rok vydání: 2018
Předmět:
Zdroj: The Journal of Immunology. 200:99.3-99.3
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.200.supp.99.3
Popis: Gamma-IFN inducible lysosomal thiol reductase (GILT) is currently the only identified thiol reductase that has optimal activity at acidic pH and localizes to lysosomes. GILT is constitutively expressed in antigen presenting cells (APC), is inducible by gamma-IFN, and participates in Ag processing by catalyzing the reduction of disulfide (S-S) bonds, thus facilitating the unfolding of native S-S bond containing Ag for further processing. Previous studies reported that T cells from GILT knock-out (GILT−/−) mice mounted a significantly reduced proliferative response to S-S containing protein Ag in vitro, GILT−/− APCs have a selective deficiency in presentation of some cysteine-containing epitopes from hen egg lysozyme, and GILT−/− mice exhibited a change in the pathogenic epitope of experimental autoimmune encephalomyelitis. Using MS/MS analysis, we identified a set of unique GILT-dependent, MHC-II associated-peptides in WT vs. GILT−/− mice, which we then validate by generating T cells specific to a unique GILT-dependent epitope from GILT−/− but not WT B6 mice. Our data suggests that GILT−/− mice are deficient in the generation of specific T cell epitopes due to a loss in GILT activity. This is consistent with our another on-going study where we find that GILT−/− mice failed to generate an Ab response to insulin due to inefficient processing of an S-S containing epitope in insulin. We hypothesize that in GILT−/− mice, GILT inactivation causes a change in the epitope repertoire that may lead to survival (escape from negative selection) of the T cells specific to GILT dependent epitopes in the thymus. The presence of these auto-reactive T cells might have implications for autoimmunity and autoimmune diseases.
Databáze: OpenAIRE
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