Abstract
Tumor Necrosis Factor (TNF) α is a multifunctional cytokine with pro-inflammatory and anti-inflammatory characteristics. Increasing evidence suggests that thymus-derived, natural regulatory T cells (nTreg) express a remarkably high level of TNF Receptor 2 (TNFR2) and TNFα modulates the number or function of nTreg via TNFR2 in autoimmune diseases. Nonetheless, Treg cells consist of at least nTreg and iTreg that are induced in the periphery or in vitro and two subsets may have different biological characteristics. However, the role of TNF-TNFR signaling in development and function of these iTreg cells is less clear. In this study, we systemically studied the effect of TNFα and its receptor signals on iTreg differentiation, proliferation, and function in vitro and in vivo. We further investigated the expression and requirement of TNFR1 or TNFR2 expression on iTreg by utilizing TNFR1−/− and TNFR2−/− mice. We found that exogenous TNFα facilitated iTreg differentiation and function in vitro. TNFR2 deficiency hampered iTreg differentiation, proliferation, and function, while TNFR1 deficiency decreased the differentiation of inflammatory T cells such as Th1 and Th17 cells but maintained the regulatory capabilities of iTreg both in vitro and in vivo. Using colitis model, we also revealed TNFR2 but not TNFR1 deficiency compromised the iTreg functionality. Interestingly, inflammation affects TNFR expression on nTreg but not iTreg subset. Our results demonstrate that exogenous TNFα may enhance the differentiation and function of iTreg via TNFR2 signaling. The expression of TNFR2 on Treg might be downregulated in some autoimmune diseases, accompanied by an increased level of TNFR1. Thus, TNFR2 agonists or TNFR1-specific antagonists hold a potential promise for clinical application in treating patients with autoimmune diseases.
Highlights
Tumor Necrosis Factor α (TNFα) plays critical roles in the pathogenesis of inflammatory diseases
When the mice suffered from EAE induction, natural regulatory T cells (nTreg) expressed an elevated level of TNFR1, especially higher in TNF Receptor 2 (TNFR2)−/− mice, and Discussion Through a series of observations, we have demonstrated that exogenous TNFα might increase induced Treg (iTreg) differentiation via TNFR2, which confirms previous reports related to nTreg both in human and mice[7,8]
Our findings provide compelling evidence that in the context of autoimmunity, TNFR2 is essential for promoting Treg proliferation
Summary
Tumor Necrosis Factor α (TNFα) plays critical roles in the pathogenesis of inflammatory diseases. We hypothesize that TNFα may have a different functional effect on T cells via their respective receptors. Official journal of the Cell Death Differentiation Association. Yang et al Cell Death and Disease (2019)10:27. TNFα exerts its function via two receptors, TNFR1 and TNFR2. Regulatory T cells (Treg) are the population of prototypic immunosuppressive T cells that terminate excessive autoimmune responses and maintain immune homeostasis[3,4]. The imbalance of the number and/or function of Treg and pathogenesis cells can lead to a wide variety of human autoimmune diseases, including multiple sclerosis (MS), rheumatoid arthritis (RA), and type I diabetes[5,6]
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