T Cell Recognition of Disulfide Modified Antigens

Abstract

Abstract Disulfide formation is one of the most common post-translational modifications and plays important in protein structures and functions. We discovered that the disulfide bridge was the epitope of a highly diabetogenic CD4 T cells. This is a shift from the paradigm that T cells commonly recognize the linear peptide antigens and showed a novel to create neo-epitopes. We identified in vivo that the different subsets of CD4 T cells could be stimulated by both reduced and oxidized form of the same antigens, IAPP. This suggested an imbalance in redox homeostasis may be important for T cell mediated pathogenesis. A disulfide bridge specific monoclonal antibody was created and showed extraordinary ability in preventing type 1 diabetes. The disulfide bridge specific T cells were able to be generalized another protein, CGRP. The lysosomal thiol reductase knock-out experiments showed that the reductase may be important for disulfide modified antigen generation during antigen processing. Elevating GSH levels through glutamate cysteine ligase pathway inhibited CD4 T cell response in a dose dependent manner. Although NOX attributed to the importance of hydrogen peroxide production in pancreatic beta cells, a Nox inhibitor effectively attenuated the BDC5.2.9 T cell activation. Our results shed light on how thiol-disulfide exchange reaction impacts the T cell responses. Supported by NIH R56 AI153488 NIH R21 AI149655