Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen. Export

@article{citeulike:2744911, 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.}, address = {Division of Hematology/Oncology, Department of Medicine, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.}, author = {Hou, Y. and Kavanagh, B. and Fong, L.}, citeulike-article-id = {2744911}, citeulike-linkout-0 = {http://view.ncbi.nlm.nih.gov/pubmed/18209048}, citeulike-linkout-1 = {http://www.hubmed.org/display.cgi?uids=18209048}, day = {1}, issn = {0022-1767}, journal = {Journal of immunology (Baltimore, Md. : 1950)}, keywords = {avidity, cap1, cap1-6d, cea}, month = {February}, number = {3}, pages = {1526--1534}, posted-at = {2008-05-02 11:16:09}, priority = {2}, title = {Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen.}, url = {http://view.ncbi.nlm.nih.gov/pubmed/18209048}, volume = {180}, year = {2008} }

TY - JOUR ID - citeulike:2744911 L3 - citeulike-article-id:2744911 N2 - 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. IS - 3 JF - Journal of immunology (Baltimore, Md. : 1950) SN - 0022-1767 AD - Division of Hematology/Oncology, Department of Medicine, University of California-San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. EP - 1534 TI - Distinct CD8+ T cell repertoires primed with agonist and native peptides derived from a tumor-associated antigen. VL - 180 SP - 1526 KW - avidity KW - cap1 KW - cap1-6d KW - cea AU - Hou, Y AU - Kavanagh, B AU - Fong, L PY - 2008/02/01/ UR - http://view.ncbi.nlm.nih.gov/pubmed/18209048 ER -