The formation of central CD8 T cell memory in response to infection depends on the transcription factor Tcf1 (Tcf7). Tcf1 is expressed at high levels in naive CD8 T cells but downregulated in most CD8 T cells during effector differentiation. The relevance of Tcf1 downregulation for effector differentiation and the signals controlling Tcf1 expression have not been elucidated. Here, we show that systemic inflammatory signals downregulated Tcf1 in CD8 T cells during dendritic cell vaccination and bacterial infections. The suppressive effect was mediated by the inflammatory cytokine interleukin 12 (IL-12), which acted via STAT4 in CD8 T cells. IL-12-induced Tcf1 downregulation required cell cycling, occurred at the transcriptional level, and was prevented in part by inhibiting DNA methyltransferases. Absence of Tcf1 during T cell priming circumvented the need of systemic inflammation for effector differentiation. We conclude that silencing of Tcf1 by systemic inflammation facilitates effector CD8 T cell differentiation.