Molecular Description of How MART-1 Specific T-Cell Receptors Recognize Structurally Diverse Melanoma Antigens

T cells are integral in mediating cellular immune responses against foreign pathogens and cancerous cells, and are activated by antigenic peptide-major histocomapatibility complex (pMHC) proteins. Though T cells are sensitive for specific antigens, many T cell receptors (TCR) can cross-react with multiple antigenic peptides. T cell cross-reactivity is important for initiation of immune responses against pathogens and tumors. Although TCR cross-reactivity is well appreciated, the molecular mechanisms of TCR-pMHC interactions are poorly understood. We have provided a molecular description of TCR cross-reactivity by structural and binding affinity characterization of melanoma specific TCRs bound to different MART-1/HLA-A2 ligands. MART-1 melanoma is a tumor protein presented by the class I MHC, HLA-A2. The MART-1/HLA-A2 antigens - the nonamer, AAGIGILTV (AAG) and the decamer, EAAGIGILTV (EAA) - differ only by one amino acid, yet adopt strikingly different conformations when bound, therefore making this system ideal to study cross reactivity.