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

Daniela Pais Ferreira; Joana Gomes Silva; Tania Wyss; Silvia A Fuertes Marraco; Léonardo Scarpellino; Mélanie Charmoy; Roeltje Maas; Imran Siddiqui; Li Tang; Johanna A Joyce; Mauro Delorenzi; Sanjiv A Luther; Daniel E Speiser; Werner Held

doi:10.1016/j.immuni.2020.09.005

Central memory CD8⁺ T cells derive from stem-like Tcf7^hi 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.

Affiliations

¹ Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland.
² SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, 1015 Lausanne, Switzerland.
³ Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
⁴ Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland; Department of Neuroscience (Neuroscience Research Center), Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
⁵ Institute of Bioengineering, École polytechnique fédérale de Lausanne, Lausanne, 1015, Switzerland.
⁶ Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
⁷ Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland; SIB Swiss Institute of Bioinformatics, Bioinformatics Core Facility, 1015 Lausanne, Switzerland.
⁸ Department of Oncology, University of Lausanne, 1066 Epalinges, Switzerland. Electronic address: werner.held@unil.ch.

PMID: 33128876
DOI: 10.1016/j.immuni.2020.09.005

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.

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*

Substances

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