Regulation of Interleukin-6 Receptor Signaling by TNF Receptor-Associated Factor 2 and 5 During Differentiation of Inflammatory CD4+ T Cells.

Hiroyuki Nagashima,Naoto Ishii,Takanori So

doi:10.3389/fimmu.2018.01986

Abstract

There is growing evidence that tumor necrosis factor (TNF) receptor-associated factors (TRAFs) bind to unconventional membrane-bound receptors in many cell types and control their key signaling activity, in both positive and negative ways. TRAFs function in a variety of biological processes in health and disease, and dysregulation of TRAF expression or activity often leads to a patho-physiological outcome. We have identified a novel attribute of TRAF2 and TRAF5 in interleukin-6 (IL-6) receptor signaling in CD4+ T cells. TRAF2 and TRAF5 are highly expressed by naïve CD4+ T cells and constitutively bind to the signal-transducing receptor common chain gp130 via the C-terminal TRAF domain. The binding between TRAF and gp130 limits the early signaling activity of the IL-6 receptor complex by preventing proximal interaction of Janus kinases (JAKs) associated with gp130. In this reason, TRAF2 and TRAF5 in naïve CD4+ T cells negatively regulate IL-6-mediated activation of signal transducer and activator of transcription 3 (STAT3) that is required for the development of IL-17-secreting CD4+ TH17 cells. Indeed, Traf2-knockdown in differentiating Traf5−/− CD4+ T cells strongly promotes TH17 development. Traf5−/− donor CD4+ T cells exacerbate the development of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in wild-type recipient mice. In this review, we summarize the current understanding of the role for TRAF2 and TRAF5 in the regulation of IL-6-driven differentiation of pro-inflammatory CD4+ T cells, especially focusing on the molecular mechanism by which TRAF2 and TRAF5 inhibit the JAK-STAT pathway that is initiated in the IL-6 receptor signaling complex.

Highlights

The tumor necrosis factor receptor-associated factor (TRAF) family molecules in mammals were initially discovered as cytoplasmic adaptor proteins interacting with one of the tumor necrosis factor receptor superfamily (TNFRSF) molecules, TNFR2 [1]
Mammalian TRAFs critically participate in the signal transduction by receptors, such as TNFRSF molecules, Toll-like receptors (TLRs), nucleotide binding-oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene (RIG)-I-like receptors (RLRs), interleukin receptors, interferon receptors, transforming growth factor-β (TGF-β) receptor, the T-cell receptor (TCR) and platelet receptors
By using a BAF/B03 cell line that stably expresses gp130 (BAFgp130), we examined the role for TRAF family molecules in IL6 receptor signaling and found that TRAF5 and TRAF2 inhibited signal transducer and activator of transcription 3 (STAT3) phosphorylation and cell proliferation mediated by IL-6–sIL-6R, while TRAF1, TRAF3, TRAF4, and TRAF6 did not

Summary

Introduction

The tumor necrosis factor receptor-associated factor (TRAF) family molecules in mammals were initially discovered as cytoplasmic adaptor proteins interacting with one of the tumor necrosis factor receptor superfamily (TNFRSF) molecules, TNFR2 [1]. The regulation of IL-6 receptor signaling by TRAF molecules was initially suggested by the observation that after culturing in IL-6-containing TH17 skewing condition in vitro, differentiating CD4+ T cells lacking Traf5 produced a higher amount of IL-17 than did wild-type counterparts.

Results

Conclusion