Vaccine-elicited T cells adopt an early memory-like transcriptional phenotype distinct from infection-elicited T cells

Abstract Protection from pathogens relies on both humoral (antibody-mediated) and cellular (T cell-mediated) responses. While infections robustly elicit both of these types of immunity, currently approved vaccine adjuvants largely fail to induce significant T cell responses. However, recent work by our lab and others suggests that the mechanisms governing vaccine-elicited T cells (Tvac) may be substantially different than those governing infection-elicited T cells (Tinf). We have recently demonstrated that optimal subunit vaccine-elicited T cell responses rely on different cytokine signals (IL-27 and 15) and metabolic function (oxidative phosphorylation vs. aerobic glycolysis) leading to phenotypically and functionally different outcomes (memory vs. effector). Our goal was to investigate the transcriptional programming that drives Tvac formation and function from immunization to memory timepoints. Using a single-cell RNA-seq approach along with functional assays, we compared Tvac and Tinf at various time points post-immunization or infectious challenge. Our data indicate that the gene expression of Tvac markedly diverges from Tinf at early and peak time points. Remarkably, while capable of being highly proliferative, Tvac adopt a distinct transcriptional phenotype with similarities to recently identified self-renewing stem cell memory T cells, such as TCF1 expression. This transcriptional program likely enables the persistence of Tvac in substantially greater abundance at memory time points conferring overall greater protection. Taken together, our data have identified a novel transcriptional program that supports a robust vaccine-elicited T cell response with implications for future therapeutic vaccine design.