The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/2000/1/321/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 321-334

Original Article

Activation of the p38 Mitogen-activated Protein Kinase Pathway Arrests Cell Cycle Progression and Differentiation of Immature Thymocytes In Vivo

Nicole L. Diehla, Hervé Enslenb,c, Karen A. Fortnera, Chris Merritta, Nate Stetsona, Colette Charlanda, Richard A. Flavelld,e, Roger J. Davisb,c, and Mercedes Rincóna
a Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont 05405
b Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School,
c Howard Hughes Medical Institute, Worcester, Massachusetts 01605
d Section of Immunobiology, Yale University School of Medicine,
e Howard Hughes Medical Institute, New Haven Connecticut 06520

Correspondence to: Mercedes Rincón, Immunobiology Program, Department of Medicine, Given Medical Building D-305, University of Vermont, Burlington, VT 05405. Tel:802-656-0937 Fax:802-656-3854 E-mail:mrincon{at}zoo.uvm.edu.

The development of T cells in the thymus is coordinated by cell-specific gene expression programs that involve multiple transcription factors and signaling pathways. Here, we show that the p38 mitogen-activated protein (MAP) kinase signaling pathway is strictly regulated during the differentiation of CD4-CD8- thymocytes. Persistent activation of p38 MAP kinase blocks fetal thymocyte development at the CD25+CD44- stage in vivo, and results in the lack of T cells in the peripheral immune system of adult mice. Inactivation of p38 MAP kinase is required for further differentiation of these cells into CD4+CD8+ thymocytes. The arrest of cell cycle in mitosis is partially responsible for the blockade of differentiation. Therefore, the p38 MAP kinase pathway is a critical regulatory element of differentiation and proliferation during the early stages of in vivo thymocyte development.

Key Words: transgenic mice, thymocyte development, mitosis, apoptosis, T cells


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