Central memory CD8 + T cells derive from stem-like Tcf7 hi effector cells in the absence of cytotoxic differentiation

• Published in: Immunity (Cambridge, Mass.) Mass.), 2020-11, Vol.53 (5), p.985
• Main Authors: Pais Ferreira, Daniela, Silva, Joana Gomes, Wyss, Tania, Fuertes Marraco, Silvia A, Scarpellino, Léonardo, Charmoy, Mélanie, Maas, Roeltje, Siddiqui, Imran, Tang, Li, Joyce, Johanna A, Delorenzi, Mauro, Luther, Sanjiv A, Speiser, Daniel E, Held, Werner
• Format: Article
• Language: English
• Subjects: Animals; Antigens; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell differentiation; Cell Differentiation - genetics; Cell Differentiation - immunology; Chromatin Assembly and Disassembly; Chronic infection; Cytotoxicity; Cytotoxicity, Immunologic - genetics; Differentiation; Effector cells; Fluorescent Antibody Technique; Gene Expression; Genotype & phenotype; Hepatocyte Nuclear Factor 1-alpha - chemistry; Hepatocyte Nuclear Factor 1-alpha - genetics; Hepatocyte Nuclear Factor 1-alpha - metabolism; Humans; Immunization; Immunologic Memory - genetics; Immunological memory; Immunophenotyping; Infections; Lymphocytes; Lymphocytes T; Memory cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Molecular; Pathogens; Protein Conformation; Proteins; Spleen; Spleen - immunology; Spleen - metabolism; Stem cells; Structure-Activity Relationship; T cell receptors; T Cell Transcription Factor 1 - chemistry; T Cell Transcription Factor 1 - genetics; T Cell Transcription Factor 1 - metabolism; Transcription factors; Vaccination; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2020.09.005

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 cells quantitatively yielded Tcm cells based on lineage tracing. Mechanistically, Tcf1 counteracted the differentiation of Tcf7 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.