Role of TNF-TNF Receptor 2 Signal in Regulatory T Cells and Its Therapeutic Implications

Abstract

Tumor necrosis factor α (TNFα) is a pleiotropic cytokine which signals through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Emerging evidence has demonstrated that TNFR1 is ubiquitously expressed on almost all cells, while TNFR2 exhibits a limited expression, predominantly on regulatory T cells (Tregs). In addition, the signaling pathway by sTNF via TNFR1 mainly triggers pro-inflammatory pathways, and mTNF binding to TNFR2 usually initiates immune modulation and tissue regeneration. TNFα plays a critical role in upregulation or downregulation of Treg activity. Deficiency in TNFR2 signaling is significant in various autoimmune diseases. An ideal therapeutic strategy for autoimmune diseases would be to selectively block the sTNF/TNFR1 signal through the administration of sTNF inhibitors, or using TNFR1 antagonists while keeping the TNFR2 signaling pathway intact. Another promising strategy would be to rely on TNFR2 agonists which could drive the expansion of Tregs and promote tissue regeneration. Design of these therapeutic strategies targeting the TNFR1 or TNFR2 signaling pathways holds promise for the treatment of diverse inflammatory and degenerative diseases.

Keywords: autoimmune diseases; regulatory T cells; tumor necrosis factor receptor 1; tumor necrosis factor receptor 2; tumor necrosis factor α.

Figure 1

When mTNF/TNF receptor 2 (TNFR2) is activated, the intracellular domains recruit existing cytoplasmic TNF receptor-associated factor-2 (TRAF-2)–cIAP-1–cIAP-2 complexes resulting in the initiation of both canonical and non-canonical NF-κB/Rel and MAPK pathways activation. NF-κB/Rel and MAPK pathways activate IL-2 promoter and trigger IL-2 expression. NF-κB pathways also transcript genes associated with cell survival and cell proliferation. So, mTNF/TNFR2 signaling can enhance expansion and stability of Tregs and increase Treg sensitivity to low level of IL-2. It also activates the reciprocal PI3K/Akt pathway. Activation of Akt signaling impairs Th17 differentiation, correlated with an increased phosphorylation of STAT5 (143). When soluble TNFα (sTNFα)/TNFR1 is activated, the intracellular domains interact with TRADD, which receptor interacting protein-1 (RIP-1) and TRAF-2 to form Signal complex I, then further triggering extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinase (JNK). The mechanisms of TNFR1 on Th17 differentiation are still unclear. These transcription factors might phosphorylate STAT3, upregulate the level of ROR-γt, and increase IL-17 production.

Figure 2

When the TNF receptor 2 (TNFR2) signaling pathway is activated, it increases Tregs stability, responses to TCR stimulation, expansion, and function. It enhances Tregs and effector T cells to produce IL-2 and promotes the sensitivity of Tregs to IL-2. IL-2 can inhibit Th17 cells differentiation and the effect of TNFR2 signaling on Tregs. Under inflammatory condition, mTNFR2 can shed to sTNFR2, sTNFR2 neutralizes TNF and hampers IL-6 expression.