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Distinct CD8⁺ T Cell Repertoires Primed with Agonist and Native Peptides Derived from a Tumor-Associated Antigen¹

Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA 94143

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 Vβ 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 Vβ1-J2 with homogenous CDR3 lengths. In contrast, the majority of Cap1-CTLs use different Vβ1 genes and also had diverse CDR3 lengths. 6D-CTLs produce IFN- 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.

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 American Cancer Society Institutional Research Award and National Institutes of Health R01 CA102303.

² Y.H. and B.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Lawrence Fong, University of California, 513 Parnassus Avenue, Box 0511, San Francisco, CA 94143. E-mail address: Lawrence.Fong{at}ucsf.edu

⁴ Abbreviations used in this paper: TAA, tumor-associated Ag; CEA, carcinoembryonic Ag; DC, dendritic cell; SSP, sequence-specific primers.

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