title: TRAF6 is required for generation of the B-1a B cell compartment as well as T cell-dependent and -independent humoral immune responses.
abstract: TNF receptor superfamily members, such as CD40 and the Toll-like receptors (TLRs), regulate many aspects of B cell differentiation and activation. TRAF6 is an intracellular signaling adaptor molecule for these receptors, but its role in B cells has not been clarified by previous genetic approaches, as the systemic deletion of the TRAF6 gene results in perinatal lethality. Here we show that B cell-specific TRAF6 deficiency results in a reduced number of mature B cells in the bone marrow and spleen. Optimal T cell-dependent (TD) antigen responses, as characterized by isotype switching and long-lived plasma cell generation, are also impaired in B cell-specific TRAF6-deficient mice. B cell-specific TRAF6-deficient mice also exhibit lower levels of serum IgM and IgG2b and defective antigen-specific IgM production in response to T cell-independent (TI) antigens. Unexpectedly, TRAF6-deficient B cell progenitors are unable to generate CD5(+) B-1 cells. These results reveal critical roles for TRAF6 in TD and TI humoral immune responses and in inductive fate decisions necessary to generate the B-1 B cell compartment.
authors.affiliation: Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan. takashik@bioreg.kyushu-u.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Tae Soo
authors.initials: TS
authors.lastname: Kim
authors.forename: Anand
authors.initials: A
authors.lastname: Jacob
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walsh
authors.forename: Yuho
authors.initials: Y
authors.lastname: Kadono
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Fuentes-Pananá
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yoshioka
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tsuneyasu
authors.initials: T
authors.lastname: Kaisho
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: John G
authors.initials: JG
authors.lastname: Monroe
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000502:physiology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000378:metabolism; D005434:Flow Cytometry; D007114:Immunization; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D019013:CD40 Antigens; D016207:Cytokines; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D019426:Integrases; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C045073:Cre recombinase