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Original Article

^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
Immunobiology Program, Department of Medicine, Given Medical Building D-305, University of Vermont, Burlington, VT 05405.802-656-3854802-656-0937

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

Abbreviations used in this paper: BrdU, bromodeoxyuridine; DN, double negative; DP, double positive; ERK, extracellular signal regulatory kinase; FTOC, fetal thymocyte development organ culture; GST, glutathione S-transferase; JNK, c-Jun NH₂-terminal kinase; HSA, heat stable antigen; MAP, mitogen-activated kinase; MKK, MAP kinase kinase; RAG, recombination activating gene; TUNEL, terminal deoxynucleotidyl transferase–mediated FITC-dUTP nick end labeling.

© 2000 The Rockefeller University Press

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