Vaccine adjuvant-elicited CD8+ T cell immunity is co-dependent on T-bet and FOXO1

T-bet and FOXO1 are transcription factors canonically associated with effector and memory T cell fates, respectively. During an infectious response, these factors direct the development of CD8+ T cell fates, where T-bet deficiency leads to ablation of only short-lived effector cells, while FOXO1 deficiency results in selective loss of memory. In contrast, following adjuvanted subunit vaccination in mice, both effector- and memory-fated T cells are compromised in the absence of either T-bet or FOXO1. Thus, unlike responses to challenge with Listeria monocytogenes, productive CD8+ T cell responses to adjuvanted vaccination require coordinated regulation of FOXO1 and T-bet transcriptional programs. Single-cell RNA sequencing analysis confirms simultaneous T-bet, FOXO1, and TCF1 transcriptional activity in vaccine-elicited, but not infection-elicited, T cells undergoing clonal expansion. Collectively, our data show that subunit vaccine adjuvants elicit T cell responses dependent on transcription factors associated with effector and memory cell fates. [Display omitted] •A memory phenotype predominates in vaccine adjuvant-elicited CD8+ T cells•Adjuvant-elicited CD8+ T cells require both T-bet and FOXO1 transcription factors•Consequently, these T cells express dual effector and memory transcriptional programs•CD8 responses to mRNA-lipid nanoparticle vaccines also require T-bet and FOXO1 In T cells responding to infection, T-bet directs the formation of effector cells but not memory, while FOXO1 directs that of memory but not effectors. However, Ivanova et al. show that following adjuvanted vaccine administration, effector and memory T cell formation is compromised in the absence of T-bet or FOXO1.