title: Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen.
abstract: Heteroclitic peptides are used to enhance the immunogenicity of tumor-associated Ags to break T cell tolerance to these self-proteins. One such altered peptide ligand (Cap1-6D) has been derived from an epitope in human carcinoembryonic Ag, CEA(605-613) (Cap1). Clinical responses have been seen in colon cancer patients receiving a tumor vaccine comprised of this altered peptide. Whether Cap1-6D serves as a T cell agonist for Cap1-specific T cells or induces different T cells is unknown. We, therefore, examined the T cell repertoires elicited by Cap1-6D and Cap1. Human CTL lines and clones were generated with either Cap1-6D peptide (6D-CTLs) or Cap1 peptide (Cap1-CTLs). The TCR Vbeta usage and functional avidity of the T cells induced in parallel against these target peptides were assessed. The predominant CTL repertoire induced by agonist Cap1-6D is limited to TCR Vbeta1-J2 with homogenous CDR3 lengths. In contrast, the majority of Cap1-CTLs use different Vbeta1 genes and also had diverse CDR3 lengths. 6D-CTLs produce IFN-gamma in response to Cap1-6D peptide with high avidity, but respond with lower avidity to the native Cap1 peptide when compared with the Cap1-CTLs. Nevertheless, 6D-CTLs could still lyse targets bearing the native epitope. Consistent with these functional results, 6D-CTLs possess TCRs that bind Cap-1 peptide/MHC tetramer with higher intensity than Cap1-CTLs but form less stable interactions with peptide/MHC as measured by tetramer decay. These results demonstrate that priming with this CEA-derived altered peptide ligand can induce distinct carcinoembryonic Ag-reactive T cells with different functional capacities.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Yafei
authors.initials: Y
authors.lastname: Hou
authors.forename: Brian
authors.initials: B
authors.lastname: Kavanagh
authors.forename: Lawrence
authors.initials: L
authors.lastname: Fong
mesh_terms: D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D045142:Cross-Priming; D000939:Epitopes / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000276:immunology* / Q000494:pharmacology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; C405522:CAP1-6D; D002272:Carcinoembryonic Antigen; D000939:Epitopes; D009842:Oligopeptides; D016693:Receptors, Antigen, T-Cell, alpha-beta