Central memory CD8+ T cells derive from stem-like Tcf7hi effector cells in the absence of cytotoxic differentiation

Abstract

Central memory CD8⁺ T cells (Tcm) control systemic secondary infections and can protect from chronic infection and cancer as a result of their stem-cell-like capacity to expand, differentiate, and self-renew. Central memory is generally thought to emerge following pathogen clearance and to form based on the de-differentiation of cytolytic effector cells. Here, we uncovered rare effector-phase CD8⁺ T cells expressing high amounts of the transcription factor Tcf7 (Tcf1) that showed no evidence of prior cytolytic differentiation and that displayed key hallmarks of Tcm cells. These effector-phase Tcf7^hi cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7^hi cells and sustained the expression of conserved adult stem-cell genes that were critical for CD8⁺ T cell stemness. The discovery of stem-cell-like CD8⁺ T cells during the effector response to acute infection provides an opportunity to optimize Tcm cell formation by vaccination.

Keywords: CD8(+) T cells; Granzyme; LCMV infection; T cell factor 1 (Tcf1) (Tcf7); central memory; effector differentiation; stemness; vaccination.