Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-bet Transcription Factor

SummaryAs acute infections resolve, effector CD8+ T cells differentiate into interleukin-7 receptorlo (IL-7Rlo) short-lived effector cells (SLECs) and IL-7Rhi memory precursor effector cells (MPECs) capable of generating long-lived memory CD8+ T cells. By using another SLEC marker, KLRG1, we found that KLRG1hi effector cells began appearing early during infection and were committed to downregulating IL-7R. Unlike IL-7Rhi MPECs, KLRG1hi IL-7Rlo SLECs relied on IL-15, but IL-15 could not sustain their long-term maintenance or homeostatic turnover. The decision between SLEC and MPEC fates was regulated by the amount of inflammatory cytokines (i.e., IL-12) present during T cell priming. According to the amount of inflammation, a gradient of T-bet was created in which high T-bet expression induced SLECs and low expression promoted MPECs. These results elucidate a mechanism by which the innate immune system sets the relative amounts of a lineage-determining transcription factor in activated CD8+ T cells and, correspondingly, regulates their memory cell potential.