title: Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins.
abstract: 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-kappaB). 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-kappaB activation, possibly through downmodulating pre-TCR signaling in DP thymocytes.
authors.affiliation: Department of Microbiology, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Huang
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kitaura
authors.forename: Ihnkyung
authors.initials: I
authors.lastname: Jang
authors.forename: Mayumi
authors.initials: M
authors.lastname: Naramura
authors.forename: Hemanta H
authors.initials: HH
authors.lastname: Kole
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Qin
authors.forename: Mark S
authors.initials: MS
authors.lastname: Schlissel
authors.forename: Hua
authors.initials: H
authors.lastname: Gu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000819:agonists; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; C493849:Cbl protein, mouse