The influence of the MAPK pathway on T cell lineage commitment.
During development, progenitor thymocytes differentiate into either CD4 or CD8 T cells, and this fate decision depends on the specificity of the T cell antigen receptor (TCR) for MHC class II or class I molecules. Based on the mechanisms of fate specification known for simple metazoan organisms, we sought to determine whether the extracellular signal-related kinases (ERKs) play a role in T cell differentiation and lineage commitment. Using a dominant gain-of-function mutant of the erk2 gene, we show that differentiation into the CD4 lineage is favored. We also show that, conversely, the addition of a pharmacological inhibitor of the ERK pathway favors differentiation into the CD8 lineage. We present a quantitative selection model that incorporates these results as well as those of recent reports on the role of Notch in T cell lineage specification.
Sharp
L L
LL
The Department of Biology and the Cancer Center, University of California, San Diego, La Jolla 92093-0687, USA.
Schwarz
D A
DA
Bott
C M
CM
Marshall
C J
CJ
Hedrick
S M
SM
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D051880:Receptors, Notch; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology; D013950:Thymus Gland / Q000166:cytology*
D004791:Enzyme Inhibitors; D005419:Flavonoids; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D051880:Receptors, Notch; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one