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

Wai W Lin1, Zuoan Yi2, Laura L Stunz2

  • 1Graduate Immunology Program, University of Iowa, Iowa City, IA 52242, USA.

Science Signaling
|September 3, 2015
PubMed

Insights

Tumor necrosis factor receptor-associated factor 3 (TRAF3) normally limits plasma cell numbers by inhibiting interleukin-6 (IL-6) signaling. Loss of TRAF3 increases plasma cells, a process reversed by removing IL-6.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Tumor necrosis factor receptor-associated factor 3 (TRAF3) is an adaptor protein regulating B cell survival and signaling pathways.
  • Loss-of-function mutations in TRAF3 are linked to B cell malignancies like multiple myeloma.
  • Interleukin-6 (IL-6) is a key cytokine supporting plasma cell differentiation and survival.

Purpose of the Study:

  • To investigate the role of TRAF3 in regulating plasma cell numbers and its connection to IL-6 signaling.
  • To elucidate the molecular mechanisms by which TRAF3 influences IL-6 receptor (IL-6R) signaling in B cells.

Main Methods:

  • Utilized B cell-specific TRAF3-deficient mice (B-Traf3(-/-)) to study plasma cell populations.
  • Assessed the impact of IL-6 deficiency on plasma cell numbers in B-Traf3(-/-) mice.
  • Investigated the interaction between TRAF3, PTPN22, Janus-activated kinase 1 (Jak1), and STAT3 phosphorylation in IL-6R signaling.

Main Results:

  • B-Traf3(-/-) mice exhibited a twofold increase in plasma cells compared to controls.
  • TRAF3-deficient B cells showed heightened responsiveness to IL-6.
  • Genetic deletion of IL-6 normalized plasma cell numbers in B-Traf3(-/-) mice.
  • TRAF3 was found to inhibit IL-6R signaling by promoting PTPN22 association with Jak1, thereby blocking STAT3 phosphorylation.
  • PTPN22 deficiency also led to increased plasma cell numbers, supporting TRAF3's inhibitory role.

Conclusions:

  • TRAF3 and PTPN22 function as inhibitors of IL-6R signaling within B cells.
  • TRAF3 plays a previously unrecognized role in controlling plasma cell differentiation.
  • These findings offer new insights into the regulation of B cell malignancies involving TRAF3 and IL-6 pathways.

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