Vaccine-elicited T cells rely on a distinct transcriptional program from infection-elicited T cells

Abstract

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 promotes Tvac formation. Using a combined ATACseq, bulk RNA-seq and single-cell RNA-seq approach, we compared Tvac and Tinf at various time points post-immunization or infectious challenge. Our data indicate that the chromatin organization and gene expression of Tvac markedly diverges from Tinf even at early time points. Furthermore, single-cell analysis indicates that Tvac represent a unique subset of activated/memory T cells, distinct from Tinf. Remarkably, while displaying a gene signature similar to highly proliferative cells, Tvac also share transcriptional properties with recently identified stem cell memory T cells, such as oxidative phosphorylation and transcription factor TCF1 gene signatures. 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.