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J. Exp. Med.,
Volume 188, Number 10, November 16, 1998 1817-1830
By
§¶§
From the * Immunobiology Program, Department of Medicine, University of Vermont, Burlington,
Vermont 05405; the The extracellular signal-regulated kinase (ERK), the c-Jun NH2-terminal kinase (JNK), and
p38 MAP kinase pathways are triggered upon ligation of the antigen-specific T cell receptor
(TCR). During the development of T cells in the thymus, the ERK pathway is required for
differentiation of CD4 Section of Immunobiology, Yale University School of Medicine and § Howard
Hughes Medical Institute, New Haven, Connecticut 06520; the Program in Molecular Medicine,
Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School and
Howard Hughes Medical Institute, Worcester, Massachusetts 01605; and the ¶ Centre de Biochimie,
UMR 134, Parc Valrose, 06108 Nice Cedex 2, France
CD8 into CD4+CD8+ double positive (DP) thymocytes, positive selection of DP cells, and their maturation into CD4+ cells. However, the ERK pathway is not
required for negative selection. Here, we show that JNK is activated in DP thymocytes in vivo
in response to signals that initiate negative selection. The activation of JNK in these cells appears to be mediated by the MAP kinase kinase MKK7 since high levels of MKK7 and low levels of Sek-1/MKK4 gene expression were detected in thymocytes. Using dominant negative
JNK transgenic mice, we show that inhibition of the JNK pathway reduces the in vivo deletion
of DP thymocytes. In addition, the increased resistance of DP thymocytes to cell death in these
mice produces an accelerated reconstitution of normal thymic populations upon in vivo DP
elimination. Together, these data indicate that the JNK pathway contributes to the deletion of
DP thymocytes by apoptosis in response to TCR-derived and other thymic environment-
mediated signals.
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