Research ArticleImmunology

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

Sci. Signal.  01 Sep 2015:
Vol. 8, Issue 392, pp. ra88
DOI: 10.1126/scisignal.aaa5157

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TRAF3 restrains plasma cells

Upon exposure to antigen, B cells differentiate to generate antibody-secreting cells called plasma cells. Multiple myeloma is an incurable malignancy characterized by the accumulation of abnormal numbers of plasma cells. Noting that mutations in the gene encoding the adaptor protein TRAF3 are associated with some cases of multiple myeloma, Lin et al. found that plasma cell numbers were increased in mice with a B cell–specific deficiency in TRAF3. Loss of TRAF3 in B cells resulted in increased responsiveness to the cytokine IL-6, which mediates the development and survival of plasma cells under normal conditions. In B cells from wild-type mice, TRAF3 associated with a phosphatase that targeted a transcription factor downstream of the IL-6 receptor, suggesting that TRAF3 limits the accumulation of plasma cells by inhibiting IL-6 signaling.

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.

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