The transcription factor T cell factor 1 (TCF1) expression is elevated in vaccine-elicited CD8+ T cells and negatively regulated by T-bet

Abstract

Abstract T cells that express high levels of TCF1 display stem cell-like properties and give rise to effector-like cells that protect during chronic infections and cancer. Due to their increased responsiveness to checkpoint blockade, TCF1hi T cells are now recognized as promising targets for immunotherapies. We found that adjuvanted subunit vaccine-elicited T cells (Tvac) express significantly higher levels of TCF1 than T cells responding to infections (Tinf). In exploring the underlying causes for such high expression of TCF1 in Tvac, we examined the role of sustained TCR and inflammatory mediators in Tvac TCF1 regulation. Using Nr4a3-Tocky reporter mice and pMHCI antibody blockade, we found that TCR mediated signals regulate Tvac TCF1 to a limited degree. In line with previous reports, TCF1 expression in Tvac inversely correlated with adjuvant-elicited pro-inflammatory signals, increasing concomitantly with the rapid decline of cytokines after adjuvant administration. Further, the addition of TLR9 ligand CpG increased inflammatory cytokine production as it reduced TCF1 expression. However, in contrast to previous work, anti-IL-12 or anti-IFNγ treatment failed to reverse the lower TCF1 expression induced by CpG. More surprisingly, we found that Tvac TCF1 is regulated independently of Foxo1 even while Foxo1 plays its canonical role in facilitating TCF1 expression under inflammatory conditions. Inflammation does however negatively regulate TCF1 in a T-bet dependent manner, such that T-bet KO Tvac maintained high TCF1 expression even when inflammation was increased. Our data highlight differences in the transcriptional regulation of vaccine- and infection-elicited T cells and provide insights into the mechanism of TCF1 regulation.