The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development

Wai W Lin; Zuoan Yi; Laura L Stunz; Christian J Maine; Linda A Sherman; Gail A Bishop

doi:10.1126/scisignal.aaa5157

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The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development

Journal article

Open access

Peer reviewed

The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development

Wai W Lin, Zuoan Yi, Laura L Stunz, Christian J Maine, Linda A Sherman and Gail A Bishop

Science signaling, Vol.8(392), pp.ra88-ra88

09/01/2015

DOI: 10.1126/scisignal.aaa5157

PMCID: PMC4720969

PMID: 26329582

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Abstract

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.

Receptors, Interleukin-6 - genetics

Humans

Protein Tyrosine Phosphatase, Non-Receptor Type 22 - genetics

Signal Transduction - genetics

Mice, Knockout

Signal Transduction - immunology

Animals

Protein Tyrosine Phosphatase, Non-Receptor Type 22 - immunology

TNF Receptor-Associated Factor 3 - genetics

TNF Receptor-Associated Factor 3 - immunology

Receptors, Interleukin-6 - immunology

Mice

Plasma Cells - immunology

Details

Title: Subtitle: The adaptor protein TRAF3 inhibits interleukin-6 receptor signaling in B cells to limit plasma cell development
Creators: Wai W Lin - Graduate Immunology Program, University of Iowa, Iowa City, IA 52242, USA
Zuoan Yi - Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Laura L Stunz - Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA
Christian J Maine - Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA
Linda A Sherman - Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA
Gail A Bishop - 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
Resource Type: Journal article
Publication Details: Science signaling, Vol.8(392), pp.ra88-ra88
DOI: 10.1126/scisignal.aaa5157
PMID: 26329582
PMCID: PMC4720969
NLM abbreviation: Sci Signal
ISSN: 1945-0877
eISSN: 1937-9145
Publisher: United States
Grant note: P30 ES005605 / NIEHS NIH HHS R01 AI028847 / NIAID NIH HHS T32 AI007260 / NIAID NIH HHS I01 BX001702 / BLRD VA P30 CA086862 / NCI NIH HHS P50 CA097274 / NCI NIH HHS AI28847 / NIAID NIH HHS P50 CA97274 / NCI NIH HHS DK050824 / NIDDK NIH HHS P30CA086862 / NCI NIH HHS R01 DK050824 / NIDDK NIH HHS R01 CA099997 / NCI NIH HHS R56 AI028847 / NIAID NIH HHS
Language: English
Date published: 09/01/2015
Academic Unit: Microbiology and Immunology; President
Record Identifier: 9984001201902771

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