Activated CD8+ T cells discriminate infected and tumor cells from normal self by recognizing MHC class I-bound peptides on the surface of antigen-presenting cells. The mechanism by which MHC class I molecules select optimal peptides against a background of prevailing suboptimal peptides and in a considerably proteolytic ER environment remained unknown. Here, we identify protein disulfide isomerase (PDI), an enzyme critical to the formation of correct disulfide bonds in proteins, as a component of the peptide-loading complex. We show that PDI stabilizes a peptide-receptive site by regulating the oxidation state of the disulfide bond in the MHC peptide-binding groove, a function that is essential for selecting optimal peptides. Furthermore, we demonstrate that human cytomegalovirus US3 protein inhibits CD8+ T cell recognition by mediating PDI degradation, verifying the functional relevance of PDI-catalyzed peptide editing in controlling intracellular pathogens. These results establish a link between thiol-based redox regulation and antigen processing.
|Number of pages||14|
|Publication status||Published - 2006 Oct 20|
Bibliographical noteFunding Information:
We thank Y. Nomura for PDI cDNA constructs, M. Theobald for MZ1851 RC cell lines, and P. Cresswell for anti-tapasin antibodies. We also thank Drs. L. Ruddock, T. Dick, and P. Cresswell for helpful discussions. This work was supported by National Creative Research Initiative Program of MOST/KOSEF. E.K. was supported by the BK21 fellowship.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)