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CD8⁺ T Cell Responses to a Viral Escape Mutant Epitope: Active Suppression via Altered SHP-1 Activity¹

Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322

One mechanism viruses use to subvert immune surveillance is through mutation of MHC contact residues of antigenic epitopes that weaken T cell recognition to the point that the immune system is ignorant of the infection. However, in contrast to ignorance, results presented herein demonstrate that intracellular signaling does occur upon stimulation with a lymphocytic choriomeningitis virus-derived escape mutant as demonstrated by the sustained activation of Src homology 2 domain-containing protein tyrosine phosphatase (SHP-1). In addition to the increased SHP-1 activity, we found that the mutated epitope failed to induce oxidation of SHP-1, further enhancing enzymatic activity. Sustained activation of SHP-1 in a reduced form correlated with ERK and early growth response gene 1 activation and failure of T cells to commit to the effector lineage. Thus, instead of immune ignorance, these studies demonstrate the activation of a negative signaling pathway that actively suppresses T cell responses and limits recognition of viral escape mutants.

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 National Institutes of Health Grant AI056017.

² Address correspondence and reprint requests to Brian D. Evavold, Department of Microbiology and Immunology, Emory University, 1510 Clifton Road, Atlanta, GA 30322. E-mail address: Evavold{at}microbio.emory.edu

³ Abbreviations used in this paper: SHP-1, Src homology region 2 domain-containing phosphatase; egr1, early growth response gene 1; IA, iodoacetamide; LCMV, lymphocytic choriomeningitis virus; MFI, mean fluorescence intensity; p-ERK, phospho-ERK; qPCR, quantitative PCR; ROS, reactive oxygen species; Tg, transgenic; WT, wild type; MnTBAP, Mn(III)-tetrakis(4-benzoic acid)porphyrin; PEO, polyethyleneoxide.