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

Immunity. 2020 Nov 17;53(5):985-1000.e11. doi: 10.1016/j.immuni.2020.09.005. Epub 2020 Oct 30.


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 Tcf7hi cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7hi 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology*
  • Chromatin Assembly and Disassembly
  • Cytotoxicity, Immunologic* / genetics
  • Fluorescent Antibody Technique
  • Gene Expression
  • Hepatocyte Nuclear Factor 1-alpha / chemistry
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism*
  • Humans
  • Immunization
  • Immunologic Memory* / genetics
  • Immunophenotyping
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Molecular
  • Protein Conformation
  • Spleen / immunology
  • Spleen / metabolism
  • Structure-Activity Relationship
  • T Cell Transcription Factor 1 / chemistry
  • T Cell Transcription Factor 1 / genetics
  • T Cell Transcription Factor 1 / metabolism*


  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • T Cell Transcription Factor 1
  • TCF7 protein, human