Data from Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8<sup>+</sup> T Cell–Effector Responses

Abstract

<div>Abstract<p>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 ramifications on the fate of the newly primed T cell. Newly primed CD8<sup>+</sup> 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<sup>+</sup> T cells that recognize the melanoma antigen TRP1 using TRP1<sup>high</sup> or TRP1<sup>low</sup> TCRs that differ in both affinity and fine specificity. From a series of altered peptide ligands, we identified a point mutation (K8) in a nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. <i>In vitro</i>, the K8 peptide induced robust proliferation of both TRP1<sup>high</sup> and TRP1<sup>low</sup> CD8<sup>+</sup> T cells but did not induce expression of PD-1. Cytokine production from K8-stimulated TRP1 cells was minimal, whereas cytotoxicity was increased. Upon transfer into B16 tumor–bearing mice, the reference peptide (TRP1-M9)- and K8-stimulated TRP1 cells were equally effective at controlling tumor growth but accomplished this through different mechanisms. TRP1-M9–stimulated cells produced more IFNγ, whereas K8-stimulated cells accumulated to higher numbers and were more cytotoxic. We, therefore, conclude that TCR recognition of weakly binding peptides during priming can skew the effector function of tumor-specific CD8<sup>+</sup> T cells.</p></div>