The Journal of Experimental Medicine
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Published 6 July 2004. doi:10.1084/jem.20040262
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 1, 25-34
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Inactivation of c-Cbl Reverses Neonatal Lethality and T Cell Developmental Arrest of SLP-76–deficient Mice

Y. Jeffrey Chiang1, Connie L. Sommers2, Martha S. Jordan4, Hua Gu5, Lawrence E. Samelson2, Gary A. Koretzky4, and Richard J. Hodes1,3

1 Experimental Immunology Branch, 2 Laboratory of Cellular and Molecular Biology, National Cancer Institute, and 3 National Institute on Aging, National Institutes of Health, Bethesda, MD 20892
4 Signal Transduction Program, Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104
5 Department of Microbiology, Columbia University, New York, NY 10032

Address correspondence to Y. Jeffrey Chiang, Experimental Immunology Branch, Building 10, Room 4B36, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Phone: (301) 496-1376; Fax: (301) 496-0887; email: chiangj{at}mail.nih.gov

c-Cbl is an adaptor protein that negatively regulates signal transduction events involved in thymic-positive selection. To further characterize the function of c-Cbl in T cell development, we analyzed the effect of c-Cbl inactivation in mice deficient in the scaffolding molecule SLP-76. SLP-76–deficient mice show a high frequency of neonatal lethality; and in surviving mice, T cell development is blocked at the DN3 stage. Inactivation of c-cbl completely reversed the neonatal lethality seen in SLP-76–deficient mice and partially reversed the T cell development arrest in these mice. SLP-76–/– Cbl–/– mice exhibited marked expansion of polarized T helper type (Th)1 and Th2 cell peripheral CD4+ T cells, lymphoid infiltrates of parenchymal organs, and premature death. This rescue of T cell development is T cell receptor dependent because it does not occur in recombination activating gene 2–/– SLP-76–/– Cbl–/– triple knockout mice. Analysis of the signal transduction properties of SLP-76–/– Cbl–/– T cells reveals a novel SLP-76– and linker for activation of T cells–independent pathway of extracellular signal–regulated kinase activation, which is normally down-regulated by c-Cbl.

Key Words: c-Cbl • SLP-76 • LAT • T cell development • ERK


The online version of this article contains supplemental material.

Abbreviations used in this paper: DN, double negative; DP, double positive; ERK, extracellular signal–regulated kinase; LAT, linker for activation of T cells; SP, single positive.


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