Alan M. Watson

Campbell

Cavender

Deckhut

Hemmer

Lawrence M. Mylin

Megan M. Thompson

Mylin

Schell

Sette

Tanaka

Todd D. Schell

van der Burg

van der Most

Abstract
               Altered peptide ligands (APLs) with enhanced binding to MHC class I can increase the CD8+ T cell response to native Ags, including tumor Ags. In this study, we investigate the influence of peptide–MHC (pMHC) stability on recruitment of tumor Ag-specific CD8+ T cells through cross-priming. Among the four known H-2b–restricted CD8+ T cell determinants within SV40 large tumor Ag (TAg), the site V determinant (489QGINNLDNL497) forms relatively low-stability pMHC and is characteristically immunorecessive. Absence of detectable site V–specific CD8+ T cells following immunization with wild-type TAg is due in part to inefficient cross-priming. We mutated nonanchor residues within the TAg site V determinant that increased pMHC stability but preserved recognition by both TCR–transgenic and polyclonal endogenous T cells. Using a novel approach to quantify the fraction of naive T cells triggered through cross-priming in vivo, we show that immunization with TAg variants expressing higher-stability determinants increased the fraction of site V–specific T cells cross-primed and effectively overcame the immunorecessive phenotype. In addition, using MHC class I tetramer–based enrichment, we demonstrate for the first time, to our knowledge, that endogenous site V–specific T cells are primed following wild-type TAg immunization despite their low initial frequency, but that the magnitude of T cell accumulation is enhanced following immunization with a site V variant TAg. Our results demonstrate that site V APLs cross-prime a higher fraction of available T cells, providing a potential mechanism for high-stability APLs to enhance immunogenicity and accumulation of T cells specific for the native determinant.</jats:p

Crossref

The Journal of Immunology

Modification of a Tumor Antigen Determinant To Improve Peptide/MHC Stability Is Associated with Increased Immunogenicity and Cross-Priming a Larger Fraction of CD8+ T Cells

Modification of a Tumor Antigen Determinant To Improve Peptide/MHC Stability Is Associated with Increased Immunogenicity and Cross-Priming a Larger Fraction of CD8
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Modification of a Tumor Antigen Determinant To Improve Peptide/MHC Stability Is Associated with Increased Immunogenicity and Cross-Priming a Larger Fraction of CD8 +

Abstract

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