Transmembrane TNF-TNFR2 Impairs Th17 Differentiation by Promoting Il2 Expression

Area of Science:

• Immunology
• Cellular Biology
• Autoimmunity Research

Background:

• Interleukin-2 (IL-2) plays a dual role in autoimmunity, while anti-TNF therapies have unpredictable outcomes.
• Understanding TNF's regulation of IL-2 is crucial for managing autoimmune diseases.
• Transmembrane TNF (tmTNF) binds TNFR2, and soluble TNF (sTNF) binds TNFR1.

Purpose of the Study:

• To investigate the role of tmTNF/TNFR2 signaling in regulating IL-2 production in CD4(+) T cells.
• To determine the impact of tmTNF/TNFR2 signaling on T helper 17 (Th17) cell differentiation.
• To elucidate the mechanisms by which TNF influences IL-2 and Th17 cell balance.

Main Methods:

• Generated genetically modified mice lacking TNFR1, TNFR2, or both, including Il2-GFP reporter strains.
• Utilized tmTNF Foxp3 reporter mice and pharmacological TNF blockade (etanercept, XPro1595).
• Assessed IL-2 promoter activity, mRNA stability, Th17 cell differentiation, STAT3/STAT5 activity, and IL-17 production in vitro and in vivo.

Main Results:

• CD4(+) T cell-intrinsic tmTNF/TNFR2 signaling stimulates IL-2 production by enhancing promoter activity and mRNA stability.
• Impaired tmTNF/TNFR2 signaling, but not sTNF/TNFR1, promotes Th17 cell differentiation.
• Loss of TNFR2 function leads to increased IL-17 production, linked to elevated STAT3 and reduced STAT5 activity, which is reversible with exogenous IL-2.

Conclusions:

• CD4(+) T cell-intrinsic tmTNF/TNFR2 signaling is essential for promoting IL-2 production, thereby inhibiting Th17 cell generation independently of Foxp3.
• Selective blockade of tmTNF/TNFR2 signaling in CD4(+) T cells can promote Th17 differentiation.
• These findings highlight a critical pathway for controlling Th17-mediated autoimmunity via the tmTNF/TNFR2-IL-2 axis.