Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity.
- Kavazović I Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia.
- Han H Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
- Balzaretti G Department of Clinical Immunology and Rheumatology, AMC Amsterdam, Amsterdam, the Netherlands.
- Slinger E Department of Experimental Immunology, AMC Amsterdam, Amsterdam, the Netherlands.
- Lemmermann NAW Institute for Virology and Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg University, Mainz, Germany.
- Ten Brinke A Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, AMC Amsterdam, Amsterdam, the Netherlands.
- Merkler D Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
- Koster J Department of Oncogenomics, AMC Amsterdam, Amsterdam, the Netherlands.
- Bryceson YT Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
- de Vries N Department of Clinical Immunology and Rheumatology, AMC Amsterdam, Amsterdam, the Netherlands.
- Jonjić S Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia.
- Klarenbeek PL Department of Clinical Immunology and Rheumatology, AMC Amsterdam, Amsterdam, the Netherlands.
- Polić B Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia.
- Eldering E Department of Experimental Immunology, AMC Amsterdam, Amsterdam, the Netherlands.
- Wensveen FM Department of Histology and Embryology, University of Rijeka, Rijeka, Croatia.
- 2020-03-18
Published in:
- PLoS biology. - 2020
Animals
Antigenic Variation
Apoptosis
CD8-Positive T-Lymphocytes
Cell Survival
Cells, Cultured
Clonal Selection, Antigen-Mediated
Gene Expression Regulation
Immunologic Memory
Lymphocyte Activation
Mice
Precursor Cells, T-Lymphoid
Proto-Oncogene Proteins c-bcl-2
Receptors, Antigen, T-Cell
Signal Transduction
T-Box Domain Proteins
English
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1371/journal.pbio.3000648
- PMID 32182234
- Persistent URL
- https://sonar.ch/global/documents/194536
Statistics
Document views: 11
File downloads:
- fulltext.pdf: 0