1. Altered Binding of Tumor Antigenic Peptides to MHC Class I Affects CD8 + T Cell-Effector Responses.
- Author
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Clancy-Thompson E, Devlin CA, Tyler PM, Servos MM, Ali LR, Ventre KS, Bhuiyan MA, Bruck PT, Birnbaum ME, and Dougan SK
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, Melanoma, Experimental pathology, Mice, Inbred C57BL, Mice, Transgenic, Oligopeptides chemistry, Oligopeptides genetics, Oligopeptides metabolism, Programmed Cell Death 1 Receptor metabolism, Antigens, Neoplasm metabolism, CD8-Positive T-Lymphocytes immunology, Histocompatibility Antigens Class I metabolism, Melanoma, Experimental immunology
- Abstract
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
+ 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 nonanchor residue that, when analyzed crystallographically and biophysically, destabilized the peptide interaction with the MHC binding groove. In vitro , the K8 peptide induced robust proliferation of both TRP1high and TRP1low CD8+ 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+ T cells., (©2018 American Association for Cancer Research.)- Published
- 2018
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