Background/Purpose: Tumor Necrosis Factor (TNF) α exerts it pro-inflammatory or anti-inflammatory function. This study hypothesizes that TNFα has multi-function through binding the different receptor 1 and 2 (TNFR1 and TNFR2) and different signal pathways affect the development and function of induced regulatory T cells (Tregs) and Th cells.

Methods: iTreg and Th cells were differentiated in vitro and in vivo in the presence or absence of TNF. We also used TNFR1^-/- and TNFR2^-/- mice to investigate the requirement of TNFR1 or TNFR2 expression on these cells with differentiation, proliferation and function.

Results: TNFα facilitated iTreg differentiation and suppressive 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 iTregs both in vitro and in vivo. Additionally, TNFR1^-/- iTregs expressed an increased level of TNFR2, while TNFR2^-/- iTregs expressed an elevated level of TNFR1. In human, Tregs from patients with multiple sclerosis (MS) and Rheumatoid Arthritis (RA) expressed an ascending level of TNFR1 but a decreased level of TNFR2.

Conclusion:

TNFα may enhance the differentiation, proliferation and function of iTregs via TNFR2 signaling while promote Th cell via TNFR1. The expression of TNFR2 on Tregs might be downregulated in some autoimmune diseases, accompanied by an increased level of TNFR1. Thus, our results suggest that TNFR2 agonists or TNFR1-specific antagonists hold a potential promise for clinical application in treating patients with autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-roles-of-tnf%ce%b1-tnfr1-and-tnf%ce%b1-tnfr2-in-the-differentiation-and-function-of-induced-cd4foxp3-treg-cells-in-autoimmune-diseases/