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Conversion of Tyrosine to the Inflammation-Associated Analog 3'-Nitrotyrosine at Either TCR- or MHC-Contact Positions Can Profoundly Affect Recognition of the MHC Class I-Restricted Epitope of Lymphocytic Choriomeningitis Virus Glycoprotein 33 by CD8 T Cells¹

Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, Victoria, British Columbia, Canada

Immunohistochemical detection of increased levels of protein-associated nitrotyrosine has become widely used as a surrogate marker of in situ inflammation. However, the potential consequences of protein-associated nitrotyrosine formation in terms of cellular immune recognition has received surprisingly little attention. Using a well-defined I-E^K-restricted epitope of pigeon cytochrome c, we previously demonstrated that conversion of a single tyrosine residue to nitrotyrosine can have a profound effect on recognition by CD4 T cells. In this study, we used the MHC class I-restricted epitope of lymphocytic choriomeningitis virus glycoprotein (gp33) to demonstrate that conversion of tyrosine to nitrotyrosine can also profoundly affect recognition of MHC class I-restricted epitopes. Conversion of the Y4 residue of the gp33 epitope to nitrotyrosine completely abrogated recognition by gp33-specific T cells from P14 TCR-transgenic mice. In contrast, CD8⁺ T cells specific for "nitrated gp33" (NY-gp33) can be readily elicited in C57BL/6 mice after immunization with NY-gp33 peptide. Interestingly, T-T hybridomas specific for NY-gp33 peptide were found to fall into two distinct subsets, being specific for NY-gp33 presented in the context of either H-2D^b or H-2K^b. This latter result is surprising in light of previous structural studies showing that Y4 comprises a critical TCR-contact residue when presented by H-2D^b but that the same residue points downward into the peptide-binding groove of the MHC when presented by H-2K^b. Together, these results indicate that nitrotyrosine formation can impact T cell recognition both directly, through alteration of TCR-contact residues, or indirectly, through alterations in MHC-contact positions.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the Canadian Institutes of Health Research (to J.R.W.).

² Current address: Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia.

³ Address correspondence and reprint requests to Dr. John R. Webb, Trev and Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Avenue, Victoria, British Columbia, Canada, V8R 6V5. E-mail address: jwebb{at}bccancer.bc.ca

⁴ Abbreviations used in this paper: NOS, NO synthase; NYP, protein-associated nitrotyrosine; PCC, pigeon cytochrome c; SFC, spot-forming cell.