Tcf1⁺ cells are required to maintain the inflationary T cell pool upon MCMV infection

Cytomegalovirus-based vaccine vectors offer interesting opportunities for T cell-based vaccination purposes as CMV infection induces large numbers of functional effector-like cells that accumulate in peripheral tissues, a process termed memory inflation. Maintenance of high numbers of peripheral CD8 T cells requires continuous replenishment of the inflationary T cell pool. Here, we show that the inflationary T cell population contains a small subset of cells expressing the transcription factor Tcf1. These Tcf1⁺ cells resemble central memory T cells and are proliferation competent. Upon sensing viral reactivation events, Tcf1⁺ cells feed into the pool of peripheral Tcf1^- cells and depletion of Tcf1⁺ cells hampers memory inflation. TCR repertoires of Tcf1⁺ and Tcf1^- populations largely overlap, with the Tcf1⁺ population showing higher clonal diversity. These data show that Tcf1⁺ cells are necessary for sustaining the inflationary T cell response, and upholding this subset is likely critical for the success of CMV-based vaccination approaches.