Understanding how T cell receptor recognition of peptide ligands shapes memory CD8+ T cell programming

Abstract CD8+ T cells are unique in effective sensing and killing of intracellular pathogen-infected cells and tumor cells. Because current vaccines are designed to induce high titer pathogen-specific antibodies for host protection, new vaccines focused on promoting effective memory CD8+ T cells are needed. Since a single naive CD8+ T cell has the potential to give rise to multiple types of progenies, it is essential to understand how naive T cells are primed to form distinct effector and memory cells. It is generally accepted that the strength of cognate antigen (Ag) stimulation determines the size of the primary response and of the memory cell pool, and that strong cognate Ag signals coupled with robust co-stimulation and cytokines altogether drive naive CD8+ T cells towards an effector rather than a memory cell fate. The current dogma also states that cognate Ag stimulation does not lead to functionally distinct subsets of memory CD8+ T cells. In contrast, however, we recently discovered that the strength and the stability of cognate Ag/MHC interactions with the T cell receptor (TCR) determine the development of memory cell functional characteristics, in particular stem-cell associated characteristics, through epigenetic imprinting. Stem cell memory CD8+ T (TSCM) cells have been shown to exhibit superior functional features, progeny potential, self-renewal capacity and longevity. Using state of the art conditional mouse models, high dimensional spectral flow cytometry, lentiviral-based inducible gain or loss of function experiments, and computational modeling approaches, we will define the features of T cell epitopes, key TCR structural modes of recognition, TCR signaling pathways, genetic and epigenetic regulators that enhance the differentiation of TSCM cells in vivo. We will validate our findings in models of chronic infections and tumors. This research directly impacts the rational design of more effective vaccines and adoptive T cell transfer therapies.