Establishment of the major compatibility complex-dependent development of CD4+ and CD8+ T cells by the Cbl family proteins.
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.
Huang
Fang
F
Department of Microbiology, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.
Kitaura
Yasuyuki
Y
Jang
Ihnkyung
I
Naramura
Mayumi
M
Kole
Hemanta H
HH
Liu
Liping
L
Qin
Haiyan
H
Schlissel
Mark S
MS
Gu
Hua
H
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
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