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© The Rockefeller University Press, 0022-1007/1998/11/1817/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 10, November 16, 1998 1817-1830

Articles

The JNK Pathway Regulates the In Vivo Deletion of Immature CD4+CD8+ Thymocytes

Mercedes Rincón*,{ddagger}, Alan Whitmarsh||, Derek D. Yang{ddagger},§, Linda Weiss*, Benoit Dérijard||,¶, Prash Jayaraj{ddagger}, Roger J. Davis||, and Richard A. Flavell{ddagger},§

From the * Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont 05405; the {ddagger} 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

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–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.

Key Words: T lymphocyte • JNK • thymic development • apoptosis

Address correspondence to Richard A. Flavell, Section of Immunobiology, Yale University School of Medicine, 310 Cedar St., FMB 412, New Haven, CT 06520. Phone: 203-737-2216; Fax: 203-785-7561; E-mail: richard.flavell{at}qm.yale.edu; or Mercedes Rincón, Department of Medicine, University of Vermont, Given Medical Building, Burlington, VT 05405. Phone: 802-656-0937; Fax: 802-656-3854; E-mail: mrincon @zoo.uvm.edu

D.D. Yang's present address is Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.

1 Abbreviations used in this paper: Cyt c, cytochrome c; DN, double negative; DP, double positive; ERK, extracellular signal-regulated kinase; GST, glutathione S-transferase; hGH, human growth hormone; JNK, c-Jun NH2-terminal kinase; SP, single positive.


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