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Establishment of the Major Compatibility Complex-Dependent Development



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Immunity 25 571 581 October 2006 2006 Elsevier Inc DOI 10 1016 j immuni 2006 08 021 Establishment of the Major Compatibility Complex Dependent Development of CD4 and CD8 T Cells by the Cbl Family Proteins Fang Huang 1 4 5 Yasuyuki Kitaura 1 4 6 IhnKyung Jang 1 4 Mayumi Naramura 2 7 Hemanta H Kole 2 Liping Liu 1 8 Haiyan Qin 1 Mark S Schlissel 3 and Hua Gu1 1 Department of Microbiology Columbia University College of Physicians and Surgeons 701 West 168th Street New York New York 10032 2 Laboratory of Immunogenetics National Institute of Allergy and Infectious Diseases National Institutes of Health Rockville Maryland 20852 3 Department of Molecular and Cell Biology University of California Berkeley Berkeley California 94720 Summary Casitas B cell lymphoma Cbl proteins are negative regulators for T cell antigen receptor TCR signaling Their role in thymocyte development remains unclear Here we show that simultaneous inactivation of c Cbl and Cbl b in thymocytes enhanced thymic negative selection and altered the ratio of CD4 and CD8 T cells Strikingly the mutant thymocytes developed into CD4 and CD8 lineage T cells independent of the major histocompatibility complex MHC indicating that the CD4 and CD8 lineage development programs are constitutively active in the absence of c Cbl and Cbl b The mutant double positive DP thymocytes exhibited spontaneous hyperactivation of nuclear factor kappa B NF kB Additionally they failed to downregulate the pre TCR and pre TCR signaling Thus our data indicate that Cbl proteins play a critical role in establishing the MHC dependent CD4 and CD8 T cell development programs They likely do so by suppressing MHC independent NF kB activation possibly through downmodulating preTCR signaling in DP thymocytes Introduction T lymphopoiesis is a sequential developmental process regulated by thymic environmental signals Fowlkes and Pardoll 1989 Love and Chan 2003 von Boehmer Correspondence hg2065 columbia edu 4 These authors contributed equally to this work 5 Present address Fu Dan University Medical School Shanghai 200032 P R China 6 Present address RIKEN BioSource Center Tsukuba Shi Ibaraki 305 0074 Japan 7 Present address Department of Medicine Evanston Northwestern Healthcare Research Institute Northwestern University Illinois 60201 8 Present address Neuroinflammation Research Center Department of Neurosciences Lerner Research Institute Cleveland Clinic 9500 Euclid Avenue Cleveland Ohio 44195 1988 The first step of T cell development involves successive rearrangements of the V D J genes in CD4 and CD8 double negative DN T precursors and only those cells with a successfully rearranged TCRb gene may develop further into CD4 and CD8 DP stage of thymocytes This step in T cell development is controlled by signaling of growth factor receptors such as interleukine 7 receptor IL 7R and pre TCR and occurs independently from the MHC because pre TCR signaling is constitutively active in the absence of the MHC Hayday et al 1999 von Boehmer and Fehling 1997 At the DP stage thymocytes may decide to become either CD4 helper T Th or CD8 cytotoxic T Tc cells and are positively and negatively selected based on the interaction between the TCR and the MHC expressed by thymic accessory cells Kaye et al 1989 Sha et al 1988 Teh et al 1988 While thymocytes expressing a TCR that recognize MHC I choose CD8 T cell fate and develop into Tc cells cells that express a TCR recognizing MHC II commit to CD4 lineage and become Th cells Cosgrove et al 1991 Grusby et al 1991 Zijlstra et al 1990 Development of CD4 and CD8 T cells is regulated by signals delivered by the TCR however it remains unclear how the incoming TCR signals are connected to the CD4 and CD8 lineage development program Current opinion indicates that engagement of the TCR with MHC initiates a TCR downstream signaling cascade starting with tyrosine phosphorylation of the immunoreceptor tyrosine based activation motifs ITAMs of the CD3 complex by the Src family tyrosine kinase Lck lymphocyte specific protein tyrosine kinase Weiss and Littman 1994 The phosphorylated ITAMs then recruit tyrosine kinase Zap70 zeta chain associated protein 70 kDa to the engaged TCR complexes leading to Zap70 activation Upon activation Zap70 phosphorylates membrane protein LAT linker for activation of T cells which then assembles a complex of multisignaling molecules including Grb2 growth factor receptor binding protein 2 Gads Grb2 related adaptor protein SLP 76 the SH2 domain containing leukocyte phosphoprotein of 76 kDa Vav PLCg 1 phospholipase Cgamma 1 and Itk interleukine 2 tyrosine kinase Koretzky and Myung 2001 Lucas et al 2003 Coordination between these signaling components leads to multiple downstream cellular responses including Ca2 mobilization cytoskeleton reorganization and activation of various nuclear factors that eventually determine the various T cell development programs The Cbl family of proteins are signaling adaptors that associate with many different receptors and intracellular signaling components Rao et al 2002 Thien et al 2001 c Cbl and Cbl b two highly homologous members of the Cbl family are coexpressed in hematopoietic lineage cells and function as E3 ubiquitin ligases Joazeiro et al 1999 Biochemical analyses reveal that Cbl proteins promote the ubiquitination of several Cbl associated proteins thereby regulating the degradation or intracellular association of these molecules Liu 2004 In the immune system protein ubiquitination has been implicated in the regulation of T lymphocyte Immunity 572 differentiation into Th2 cells as well as in the induction of immune tolerance Fang et al 2002 Naramura et al 2002 However it remains unclear whether Cbl proteins also control the development of early T cells c Cbl and Cbl b are differentially expressed in thymocytes and mature T cells Naramura et al 2002 Such developmentally regulated pattern of expression is consistent with their predominant role either in thymocyte development or in peripheral T cell activation Bachmaier et al 2000 Chiang et al 2000 Naramura et al 1998 2002 At the molecular level c Cbl and Cbl b share a high sequence homology and are coexpressed in developing thymocytes Naramura et al 2002 thus suggesting that they may have a redundant function in early T cell development and differentiation In this report we show that simultaneous ablation of c Cbl and Cbl b in thymocytes resulted in spontaneous development of CD4 and CD8 T cells in the absence of the MHC The


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