Impact of T cell receptor signaling on memory CD8+ T cell stemness

ABSTRACT CD8+ T cells' unique ability to sense and kill pathogen-infected and tumor cells makes developing human vaccines designed to induce potent CD8+ T cell memory an important necessity. In this proposal, we explore the roles of T cell receptor (TCR) signaling and peptide/MHC (pMHC) stability on generating memory CD8+ T cells. Strong cognate antigen interactions induce robust primary effector responses and generate larger pools of memory CD8+ T cells. However, whether the quality of TCR signaling and pMHC interactions can imprint distinct CD8+ T cell memory programs is not well known. Prior studies state that differences in antigen stimulation do not lead to functional differences, but our preliminary data suggest that the strength and the stability of pMHC and TCR interactions do imprint functionally distinct cellular programs in resulting memory CD8+ T cells. Using high-dimensional spectral flow cytometry, transgenic TCR and fluorescent reporter mouse models, and an inducible lentiviral-based T cell gene editing approach, we will determine whether model epitopes with distinct TCR signaling qualities can imprint distinct memory cell programs. In addition, we will characterize a subset of memory CD8+ T cells that we propose are precursors to long-lived memory and test whether these cells confer improved pathogen-specific protection. I am confident that I will successfully execute the proposed research and training plans under the mentorship of Dr. Gregoire Lauvau with the support of our collaborators, Drs. Wenjun Guo and Fabien Delahaye, experts in stem cell transduction and computational genomics, respectively. Findings from our proposed study will contribute to a better understanding of memory CD8+ T cell formation and improve rational design for CD8+ T cell-based vaccines and adoptive T cell transfer immunotherapies.