1. Academic Validation
  2. Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity

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.
Inga Kavazović 1 Hongya Han 2 3 Giulia Balzaretti 4 Erik Slinger 5 Niels A W Lemmermann 6 Anja Ten Brinke 7 Doron Merkler 8 Jan Koster 9 Yenan T Bryceson 2 3 Niek de Vries 4 Stipan Jonjić 1 Paul L Klarenbeek 4 Bojan Polić 1 Eric Eldering 5 Felix M Wensveen 1 5
Affiliations

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.

Figures
Products