Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice

The Journal of Experimental Medicine
Y Jeffrey ChiangRichard Hodes

Abstract

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.

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Citations

Feb 24, 2006·Nature Reviews. Immunology·Gary A KoretzkyMichael A Silverman
Jun 14, 2008·Nature Reviews. Immunology·Adrian ListonOwen M Siggs
Dec 17, 2008·The Journal of Biological Chemistry·Y Jeffrey ChiangRichard J Hodes
Jan 22, 2008·International Immunology·Shinya HidanoRyo Goitsuka
Jul 9, 2010·Cold Spring Harbor Perspectives in Biology·Lakshmi BalagopalanConnie L Sommers
Apr 15, 2011·PloS One·Jeffrey Chiang, Richard J Hodes
Jan 29, 2010·Seminars in Immunopathology·Romain RoncagalliMarie Malissen
Jun 15, 2010·Trends in Immunology·Romain RoncagalliBernard Malissen
Dec 6, 2014·International Immunology·Y Jeffrey Chiang, Richard J Hodes
Feb 10, 2006·The EMBO Journal·Alex BraimanLawrence E Samelson
Oct 14, 2010·Journal of Leukocyte Biology·Mario Martínez-FlorensaEnrique Aguado
Oct 11, 2005·The Biochemical Journal·Christine B F Thien, Wallace Y Langdon
Mar 9, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Melissa DohertyScott A Wetzel
Jan 5, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Haifeng SongRichard J Hodes
Aug 31, 2021·Frontiers in Immunology·Yael Dinur-SchejterPolina Stepensky

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Methods Mentioned

BETA
transgenic
ELISA
PMA
flow cytometry
electrophoresis

Software Mentioned

FlowJo
TreeStar

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