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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
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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