Tumor necrosis factor receptor-associated factor 3 is a critical regulator of B cell homeostasis in secondary lymphoid organs.
Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an adaptor protein that directly binds to a number of receptors of the tumor necrosis factor receptor (TNF-R) superfamily. Despite in vitro evidence that TRAF3 plays diverse roles in different cell types, little is known about the in vivo functions of TRAF3. To address this gap in knowledge and to circumvent the early lethal effect of TRAF3 null mutations, we generated conditional TRAF3-deficient mice. B-cell-specific Traf3(-/-) mice displayed severe peripheral B cell hyperplasia, which culminated in hyperimmunoglobulinemia and increased T-independent antibody responses, splenomegaly and lymphadenopathy. Resting splenic B cells from these mice exhibited remarkably prolonged survival ex vivo independent of B cell activating factor and showed increased amounts of active nuclear factor-kappaB2 but decreased amounts of nuclear protein kinase Cdelta. Furthermore, these mice developed autoimmune manifestations as they aged. These findings indicate that TRAF3 is a critical regulator of peripheral B cell homeostasis and may be implicated in the regulation of peripheral self-tolerance induction.
Xie
Ping
P
Department of Microbiology, The University of Iowa, Iowa City, IA 52242, USA.
Stunz
Laura L
LL
Larison
Karen D
KD
Yang
Baoli
B
Bishop
Gail A
GA
D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D053264:B-Cell Activating Factor / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D017353:Gene Deletion; D018858:Germinal Center / Q000276:immunology; D006706:Homeostasis; D006942:Hypergammaglobulinemia; D006965:Hyperplasia / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology*; D013163:Splenomegaly / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000502:physiology*; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000378:metabolism
D053264:B-Cell Activating Factor; D016328:NF-kappa B; D048008:TNF Receptor-Associated Factor 3; C491959:Tnfsf13 protein, mouse; C505720:Tnfsf13b protein, mouse; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D051745:Protein Kinase C-delta