Altered binding of tumor antigenic peptides to MHC class I affects CD8 T cell effector responses

T cell priming occurs when a naïve T cell recognizes cognate peptide-MHC complexes on an activated antigen presenting cell. The circumstances of this initial priming have dramatic ramifications on the fate of the newly primed T cell. Newly primed CD8 T cells can embark onto different trajectories, with some becoming short lived effector cells and others adopting a tissue resident or memory cell fate. To determine whether T cell priming influences the quality of the effector T cell response to tumors, we used transnuclear CD8 T cells that recognize the melanoma antigen TRP1 using TRP1high or TRP1low TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a non-anchor residue that, when analyzed crystallographically and biophysically, destabilizes the peptide interaction with the MHC binding groove. We then compared the transcriptional profiles of TRP1-specific T cells activated in vitro with M9 peptide to those activated with K8 peptide. Four samples were analyzed: TRP1high or TRP1low cells stimulated by B cells pulsed with K8 or M9 peptide for 48 hours.