The Regulation Of Transcription Factor T Cell Factor 1 (Tcf1) In Vaccine-Elicited Cd8+T Cells

Abstract Our lab has developed a subunit vaccination regimen that induces a highly robust T cell response. These vaccine-elicited CD8+ T cells (Tvac) are phenotypically, functionally and metabolically distinct from infection-elicited CD8+ T cells (Tinf). In contrast to Tinf, almost all Tvac rapidly acquire a memory phenotype (CD127hi, KLRG1lo). This suggests that Tvac could be differentially transcriptionally programmed to commit to a memory, rather than effector, cell fate. The transcription factor TCF1 (encoded by tcf7) is essential for CD8+ T cell memory in response to infection. Since high TCF1 expression is also important for the generation of stem-like T cells with long-term survival capacity and anti-tumor properties, it is now recognized as a promising target for immunotherapies. However, little is known about how TCF1 is regulated in response to subunit vaccination. We find that, in striking contrast to Tinf, TCF1 expression is actually increased in Tvac after vaccination. As others have shown, we also find that increasing inflammation during vaccination by the addition of TLR9 agonist CpG reduces TCF1 expression in Tvac, skewing their memory phenotype towards the effector phenotype (CD127lo, KLRG1hi) and compromising their long-term memory. While the loss of TCF1 in this context has conventionally been ascribed to inflammatory receptors, utilizing reporter Nur77GFP mice, we also observe an altered duration and frequency of TCR triggering in the context of inflammation. Our data indicates a complex, previously unappreciated interplay between inflammatory and TCR-mediated signals in the regulation of TCF1.