The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development.
Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an adaptor protein that inhibits signaling by CD40 and by the receptor for B cell-activating factor (BAFF) and negatively regulates homeostatic B cell survival. Loss-of-function mutations in TRAF3 are associated with human B cell malignancies, in particular multiple myeloma. The cytokine interleukin-6 (IL-6) supports the differentiation and survival of normal and neoplastic plasma cells. We found that mice with a deficiency in TRAF3 specifically in B cells (B-Traf3(-/-) mice) had about twice as many plasma cells as did their littermate controls. TRAF3-deficient B cells had enhanced responsiveness to IL-6, and genetic loss of IL-6 in B-Traf3(-/-) mice restored their plasma cell numbers to normal. TRAF3 inhibited IL-6 receptor (IL-6R)-mediated signaling by facilitating the association of PTPN22 (a nonreceptor protein tyrosine phosphatase) with the kinase Janus-activated kinase 1 (Jak1), which in turn blocked phosphorylation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Consistent with these results, the number of plasma cells in the PTPN22-deficient mice was increased compared to that in the wild-type mice. Our findings identify TRAF3 and PTPN22 as inhibitors of IL-6R signaling in B cells and reveal a previously uncharacterized role for TRAF3 in the regulation of plasma cell differentiation.
Graduate Immunology Program, University of Iowa, Iowa City, IA 52242, USA.
Wai W
WW
Lin
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Zuoan
Z
Yi
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Laura L
LL
Stunz
Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
Christian J
CJ
Maine
Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
Linda A
LA
Sherman
Graduate Immunology Program, University of Iowa, Iowa City, IA 52242, USA. Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA. Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA. Veterans Affairs Medical Center, Iowa City, IA 52246, USA. gail-bishop@uiowa.edu.
Gail A
GA
Bishop
D000818:Animals; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010950:Plasma Cells / Q000276:immunology*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000276:immunology*
C508603:IL6R protein, human; D019947:Receptors, Interleukin-6; D048008:TNF Receptor-Associated Factor 3; C090656:TRAF3 protein, human; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C516766:Ptpn22 protein, mouse