The adaptor TRAF5 limits the differentiation of inflammatory CD4+ T cells by antagonizing signaling via the receptor for IL-6

Abstract

The physiological functions of members of the tumor-necrosis factor (TNF) receptor (TNFR)–associated factor (TRAF) family in T cell immunity are not well understood. We found that in the presence of interleukin 6 (IL-6), naive TRAF5-deficient CD4+ T cells showed an enhanced ability to differentiate into the TH17 subset of helper T cells. Accordingly, TH17 cell–associated experimental autoimmune encephalomyelitis (EAE) was greatly exaggerated in Traf5−/− mice. Although it is normally linked with TNFR signaling pathways, TRAF5 constitutively associated with a cytoplasmic region in the signal-transducing receptor gp130 that overlaps with the binding site for the transcription activator STAT3 and suppressed the recruitment and activation of STAT3 in response to IL-6. Our results identify TRAF5 as a negative regulator of the IL-6 receptor signaling pathway that limits the induction of proinflammatory CD4+ T cells that require IL-6 for their development.

TRAF5-mediated Lys-63-linked Polyubiquitination Plays an Essential Role in Positive Regulation of RORγt in Promoting IL-17A Expression

“…On the other hand, some studies contribute to the conclusion that TRAF5 can act as an anti-inflammatory factor. Researchers found that naïve CD4 ϩ T cells from Traf Ϫ/Ϫ mice tend to differentiate toward Th17 cells (14), whereas B lymphocytes from Traf Ϫ/Ϫ mice could produce more cytokines, including IL-6, IL-10, and TNF-␣, after Toll-like receptor stimulation (15). It has been well established that TRAF5 is involved in the pathogenesis of several inflammatory and autoimmune diseases.…”

Cutting Edge: Ubiquitin-Specific Protease 4 Promotes Th17 Cell Function under Inflammation by Deubiquitinating and Stabilizing RORγt

“…The proinflammatory cytokines TGF-b, IL-6, IL-1b, and IL-23 are essential to Th17 cell differentiation and function (1)(2)(3)(4). Several deubiquitinases (DUBs) or E3 ligases are important regulators of Th17 cell differentiation (5)(6)(7)(8). The orphan nuclear receptor RORgt is crucial for Th17 cell development, but the modulation of its stability remains uncharacterized (2,9).…”

TNF Receptor-Associated Factor (TRAF) Signaling Network in CD4⁺ T-Lymphocytes

“…TRAF5 negatively regulates IL-6-receptor signaling (Nagashima et al 2014 (Arch and Thompson 1998;Park et al 1999;Ye et al 1999 (Stahl et al 1995). The TRAF5-binding region is located between those first two motifs, which suggests that TRAF5 inhibits the recruitment of STAT3 to these two motifs through steric hindrance in gp130 or through modulation of an optimal configuration of gp130 that might be required for activating JAK or STAT3.…”

“…Anti-CD3/CD28 stimulation significantly downregulates the Traf5 expression in wild-type CD4 + T cells, suggesting that the constitutive TRAF5-gp130 binding is critical for limiting the initial instructive IL-6 signals required for T H 17 development (Nagashima et al 2014). …”

“…The ability of Traf5 −/− naïve CD4 + T cells to differentiate into T H 17 cells is enhanced by IL-6. Accordingly, the T H 17-cell-associated experimental autoimmune encephalomyelitis (EAE) is exaggerated in Traf5 −/− mice (Nagashima et al 2014). These results demonstrate that TRAF5 limits the differentiation of inflammatory CD4 + T cells such as T H 2 and T H 17 cells.…”