1. The Catalytic Activity of the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase 3 Is Required To Sustain CD4+ CD8+ Thymocyte Survival.
- Author
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Marquis, Miriam, Daudelin, Jean-François, Boulet, Salix, Sirois, Julien, Crain, Karinn, Mathien, Simon, Turgeon, Benjamin, Rousseau, Justine, Meloche, Sylvain, and Labrecque, Nathalie
- Subjects
EXTRACELLULAR signal-regulated kinases ,MITOGEN-activated protein kinases ,PROTEIN kinases ,THYMOCYTES ,TRANSGENES ,T cell receptors ,CELL proliferation - Abstract
Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family whose function is largely unknown. Given the central role of MAPKs in T cell development, we hypothesized that ERK3 may regulate thymocyte development. Here we have shown that ERK3 deficiency leads to a 50% reduction in CD4
+ CD8+ (DP) thymocyte number. Analysis of hematopoietic chimeras revealed that the reduction in DP thymocytes is intrinsic to hematopoietic cells. We found that early thymic progenitors seed the Erk3-/- thymus and can properly differentiate and proliferate to generate DP thymocytes. However, ERK3 deficiency results in a decrease in the DP thymocyte half-life, associated with a higher level of apoptosis. As a consequence, ERK3-deficient DP thymocytes are impaired in their ability to make successful secondary T cell receptor alpha (TCRα) gene rearrangement. Introduction of an already rearranged TCR transgene restores thymic cell number. We further show that knock-in of a catalytically inactive allele of Erk3 fails to rescue the loss of DP thymocytes. Our results uncover a unique role for ERK3, dependent on its kinase activity, during T cell development and show that this atypical MAPK is essential to sustain DP survival during RAG-mediated rearrangements. [ABSTRACT FROM AUTHOR]- Published
- 2014
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