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

Alan M. Watson, Lawrence M. Mylin, Megan M. Thompson, Todd Schell

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5549-5560
Number of pages12
JournalJournal of Immunology
Volume189
Issue number12
DOIs
StatePublished - Dec 15 2012

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Cross-Priming
Neoplasm Antigens
T-Lymphocytes
Peptides
Immunization
Neoplasms
Ligands

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

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title = "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",
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.",
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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+ T cells. / Watson, Alan M.; Mylin, Lawrence M.; Thompson, Megan M.; Schell, Todd.

In: Journal of Immunology, Vol. 189, No. 12, 15.12.2012, p. 5549-5560.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 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

AU - Watson, Alan M.

AU - Mylin, Lawrence M.

AU - Thompson, Megan M.

AU - Schell, Todd

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Y1 - 2012/12/15

N2 - 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.

AB - 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.

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