Differential roles of TNFα-TNFR1 and TNFα-TNFR2 in the differentiation and function of CD4+Foxp3+ induced Treg cells in vitro and in vivo periphery in autoimmune diseases

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.

Selective Targeting of TNF Receptors as a Novel Therapeutic Approach

“…In contrast, TNFR1 deficiency resulted in reduced differentiation of inflammatory T cells, while the iTregs function was unaltered. Using a colitis model, they confirmed that TNFR2 but not TNFR1 deficiency impaired iTreg functionality (Yang et al, 2019), and proposed that TNFR2 also plays a role of iTreg function.…”

“…Whereas, the function of TNFR2 for nTregs is wellcharacterized, less is known about the impact of TNFR2 on induced Tregs (iTreg). Recently, Yang et al (2019) demonstrated that TNFR2 deficiency impeded differentiation, proliferation, and function of iTregs. In contrast, TNFR1 deficiency resulted in reduced differentiation of inflammatory T cells, while the iTregs function was unaltered.…”

CD8+CD103+ iTregs Inhibit Chronic Graft-versus-Host Disease with Lupus Nephritis by the Increased Expression of CD39

“…Treg-mediated suppression serves as a vital mechanism for the negative regulation of immune-mediated inflammation, and it features prominently in autoimmune and inflammatory disorders. 36 , 37 , 38 Several lines of experimentation have provided the proof that a lack of Tregs is the cause of fatal autoimmunity. 39 , 40 , 41 , 42 CD8+ Tregs, one subset of Tregs, have been reported to display potent therapeutic effect in some diseases, such as lupus and GVHD.…”

CD226: An Emerging Role in Immunologic Diseases

“…In 2015, Fuhrman et al found that CD226 was expressed in memory CD4 + T cells (Fuhrman et al, 2015). These abnormal cells and relative pro-inflammatory cytokines contribute to many immunologic diseases (Yang and Song Guo, 2016;Sujuan et al, 2018Sujuan et al, , 2019.…”