Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity

Inga Kavazović; Hongya Han; Giulia Balzaretti; Erik Slinger; Niels A W Lemmermann; Anja Ten Brinke; Doron Merkler; Jan Koster; Yenan T Bryceson; Niek de Vries; Stipan Jonjić; Paul L Klarenbeek; Bojan Polić; Eric Eldering; Felix M Wensveen

doi:10.1371/journal.pbio.3000648

Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity

PLoS Biol. 2020 Mar 17;18(3):e3000648. doi: 10.1371/journal.pbio.3000648. eCollection 2020 Mar.

Authors

Inga Kavazović¹, Hongya Han^{2

3}, Giulia Balzaretti⁴, Erik Slinger⁵, Niels A W Lemmermann⁶, Anja Ten Brinke⁷, Doron Merkler⁸, Jan Koster⁹, Yenan T Bryceson^{2

3}, Niek de Vries⁴, Stipan Jonjić¹, Paul L Klarenbeek⁴, Bojan Polić¹, Eric Eldering⁵, Felix M Wensveen^{1

5}

Affiliations

¹ Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia.
² Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
³ Brogelmann Research Laboratory, Department of Clinical Sciences, University of Bergen, Bergen, Norway.
⁴ Department of Clinical Immunology and Rheumatology, AMC Amsterdam, Amsterdam, the Netherlands.
⁵ Department of Experimental Immunology, AMC Amsterdam, Amsterdam, the Netherlands.
⁶ Institute for Virology and Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
⁷ Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, AMC Amsterdam, Amsterdam, the Netherlands.
⁸ Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
⁹ Department of Oncogenomics, AMC Amsterdam, Amsterdam, the Netherlands.

Abstract

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigenic Variation / immunology
Apoptosis / immunology*
CD8-Positive T-Lymphocytes / immunology*
Cell Survival / immunology
Cells, Cultured
Clonal Selection, Antigen-Mediated / genetics
Clonal Selection, Antigen-Mediated / immunology
Gene Expression Regulation / immunology
Immunologic Memory*
Lymphocyte Activation
Mice
Precursor Cells, T-Lymphoid / immunology
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / immunology
Receptors, Antigen, T-Cell / genetics
Receptors, Antigen, T-Cell / immunology
Signal Transduction
T-Box Domain Proteins / genetics
T-Box Domain Proteins / immunology*

Substances

Eomes protein, mouse
Proto-Oncogene Proteins c-bcl-2
Receptors, Antigen, T-Cell
T-Box Domain Proteins
T-box transcription factor TBX21
Bcl2 protein, mouse

Grants and funding

Funding was received from the Veni grant 91614029 to FMW (Nederlandse Organisatie voor Wetenschappelijk onderzoek, https://www.nwo.nl/); PCIG14-GA-2013-630827 to FMW (European Commission, https://ec.europa.eu/research/mariecurieactions/); University of Rijeka support grant 865.10.2101 to FMW (Zaklada Sveučilišta u Rijeci, https://www.zaklada.uniri.hr/zaklada/); IP-2016-06-8027 to FMW (Hrvatska Zaklada za Znanost, https://www.hrzz.hr/); IP-2016-06-9306 to BP (Hrvatska Zaklada za Znanost, https://www.hrzz.hr/); HR.3.2.01-0263 to BP (the European Social Fund for Croatia, http://www.esf.hr/); and KK.01.1.1.01.0006 to SJ (European Regional Development Fund for Croatia, https://strukturnifondovi.hr/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.