TRAF6 Is Required for Generation of the B-1a B Cell Compartment as well as T Cell-Dependent and -Independent Humoral Immune Responses

Takashi Kobayashi,Anand Jacob,Tae Soo Kim,Matthew C Walsh,Tsuneyasu Kaisho,Shizuo Akira,Tomoko Yoshioka,Akihiko Yoshimura,Yuho Kadono,Masahiro Yamamoto,John G Monroe,Yongwon Choi,Ezequiel Fuentes-Pananá,Wasif N Khan

doi:10.1371/journal.pone.0004736

Takashi Kobayashi, Anand Jacob + Show 12 more

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https://doi.org/10.1371/journal.pone.0004736

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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.

Highlights

Ligands for the Toll-like receptors (TLRs), such as lipopolysaccharide (LPS) and CpG-DNA, are powerful B cell mitogens, and they induce proinflammatory cytokines such as interleukin (IL)-6 and the surface molecules CD40, B-7 and MHC class II [1,2,3,4]
TNF receptor-associated factor 6 (TRAF6) is recruited to the motif PXEXXAr/Ac, which is found in the IL-1 receptorassociated kinase (IRAK) adaptor molecules and in the cytoplasmic portion of tumor necrosis factor receptor (TNFR) family members like CD40 and receptor activator of NF-kB (RANK) [11,12,13]
Purified B cells from spleen of CD19Cre/+TRAF6flox/flox mice contained almost undetectable levels of TRAF6 protein, a substantial amount of TRAF6 was present in non-B splenocytes as well as in B cells from control mice

Summary

Introduction

Ligands for the Toll-like receptors (TLRs), such as lipopolysaccharide (LPS) and CpG-DNA, are powerful B cell mitogens, and they induce proinflammatory cytokines such as interleukin (IL)-6 and the surface molecules CD40, B-7 and MHC class II [1,2,3,4]. TNF receptor-associated factor 6 (TRAF6), a member of the TRAF family of cytoplasmic adaptors, transduces signals from the TNFRs [7] as well as from the TLRs [8,9], thereby playing a critical role in innate immunity [10]. TRAF6 is recruited to the motif PXEXXAr/Ac, which is found in the IL-1 receptorassociated kinase (IRAK) adaptor molecules and in the cytoplasmic portion of TNFR family members like CD40 and receptor activator of NF-kB (RANK) [11,12,13]. The functional readouts examined were different; in addition, in one study the mutant CD40 molecule was widely expressed [14], while in the other it was expressed exclusively in B cells [15]. Neither of these studies was designed to determine CD40-independent functions of TRAF6 in B cells

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