TNF Receptor–Associated Factor 5 Limits IL-27 Receptor Signaling in CD4+ T Lymphocytes

Abstract

TNF receptor–associated factor 5 (TRAF5) restrains early signaling activity of the IL-6 receptor in naive CD4+ T cells by interacting with the shared gp130 chain, although TRAF5 was initially discovered as a cytoplasmic adaptor protein to activate signaling mediated by TNF receptor family molecules. This leads to the question of whether TRAF5 limits signaling via the receptor for IL-27, which is composed of gp130 and WSX-1. The aim of this study is to clarify the role of TRAF5 in IL-27 receptor signaling and to understand the differential role of TRAF5 on cytokine receptor signaling. We found that Traf5−/− CD4+ T cells displayed significantly higher levels of phosphorylated STAT1 and STAT-regulated genes Socs3 and Tbx21, as early as 1 h after IL-27 exposure when compared with Traf5+/+ CD4+ T cells. Upon IL-27 and TCR signals, the Traf5 deficiency significantly increased the induction of IL-10 and promoted the proliferation of CD4+ T cells. Traf5−/− mice injected with IL-27 displayed significantly enhanced delayed-type hypersensitivity responses, demonstrating that TRAF5 works as a negative regulator for IL-27 receptor signaling. In contrast, IL-2 and proliferation mediated by glucocorticoid-induced TNF receptor–related protein (GITR) and TCR signals were significantly decreased in Traf5−/− CD4+ T cells, confirming that TRAF5 works as a positive regulator for cosignaling via GITR. Collectively, our results demonstrate that TRAF5 reciprocally controls signals mediated by the IL-27 receptor and GITR in CD4+ T cells and suggest that the regulatory activity of TRAF5 in gp130 is distinct from that in TNF receptor family molecules in a T cell.

Role of tumor necrosis factor receptor-associated factor 5 in B- and T-lymphocytes

“…CD40-mediated activation of NF-κB and JNK pathways was intact in Traf5 -/-B cells. CD40-mediated Ig production and class switching in vitro were significantly reduced in Traf5 -/-B cells and mild defects in affinity maturation of IgG to a T-dependent antigen in vivo were observed in Traf5 -/mice [12,17,19]. These studies indicate that Traf5-deficiency leads to partial impairments of CD40 signaling in B cells.…”

“…GITR cross-linking on antigen-activated GITR + CD4 + T cells from Traf5 -/-DO11.10 mice displayed diminished activation of NF-κB1, p38, and ERK pathways. Consistently, Traf5-deficiency in CD4 + T cells resulted in diminished T cell proliferation and IL-2 production mediated by T cell receptor (TCR)/CD3 and GITR [19,43]. Small interfering RNA-mediated Traf5 knockdown in primary CD8 + T cells caused impaired NF-κB1 activation mediated by GITR [44].…”

“…Whereas germline deletion of Traf2 or Traf3 in mice leads to premature death with severe developmental abnormalities [14][15][16], that of Traf5 displays no obvious abnormalities [17], suggesting that TRAF5 likely plays minor roles at a steady state. However, Traf5 deficient mice showed exacerbated disease phenotypes in the context of a proinflammatory milieu [13,[18][19][20][21][22][23]. This leads to the question of how TRAF5 regulates cellular signaling in the context of inflammatory diseases.…”

OX40 Ligand-Mannose-Binding Lectin Fusion Protein Induces Potent OX40 Cosignaling in CD4⁺ T Cells

“…Preparation of recombinant proteins was previously described. 11,12) Briefly, the vector was transfected into HEK293T cells by using polyethyleneimine (#408727, Merck Millipore, Burlington, MA, U.S.A.), and then cultured in Dulbecco modified Eagle medium (043-30085, FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan) containing 2% fetal calf serum (FCS), 100 U/mL penicillin, and 100 µg/mL streptomycin for 5 to 7 d. Alternatively, a DG44-CHO cell (ATC C, CRL-9096) clone stably expressing PA-MBL-OX40L was established to produce PA-MBL-OX40L protein. Recombinant Fc fusion protein was purified from the culture supernatants by HiTrap™ rProtein A FF column (#17507901, Cytiva, Tokyo, Japan).…”

Changes in IL-27 and its effect on CD4 + T cells in patients with coronary artery disease

“…IL-27 is a heterodimer composed of P28 and EBI3 that signals to cells through its receptor. Il-27 receptor (IL-27R) is also a heterodimer composed of IL-27Rα and gP130 [9]. As an important cytokine, IL-27 is involved in the development of many human diseases, such as autoimmune diseases, infectious diseases and cancer.…”