Increasing strength of antigenic stimulation negatively impacts memory CD8 T cell formation and function during persistent viral infection

Abstract

Abstract Memory CD8 T cells are critical for keeping persistent viral infections in check. Here, we used a novel approach to directly study the impact of T cell stimulation strength on memory T cell differentiation in the setting of a persistent viral infection. Using site-directed mutagenesis, we generated a series of MPyV variants with substitutions in a subdominant Db-restricted epitope that modulated level of activation of TCR transgenic CD8 T cells specific for a corresponding epitope in SV40 Large T Antigen. By altering a subdominant epitope constituting approximately 1% of the total anti-MPyV CD8 T cell response, we avoided perturbing MPyV-associated inflammation, virus infection levels, antiviral CD4 T cell responses, and the dominant anti-MPyV CD8 T cell response. Moreover, by using physiologic numbers of naïve donor monoclonal CD8 T cells for adoptive transfer into immunocompetent C57BL/6 recipients, we also controlled for variability in naïve T cell precursor frequency and TCR affinity inherent in T cell recruitment to infection. Our data demonstrate an inverse relationship between antigenic stimulation strength and expression of memory precursor effector phenotype (CD127highKLRG1low) by virus-specific CD8 T cells during acute infection. Although stronger antigenic stimulation augmented expansion of functional CD8 T cells in acute infection, lower stimulation favored functional competence of memory antiviral CD8 T cells during persistent infection. Together, these data provide clear in vivo evidence that the strength of antigenic stimulation during recruitment of MPyV-specific CD8 T cells dictates the functional integrity of memory T cells during persistent infection.