Selective Activation of Tumor Necrosis Factor Receptor II Induces Antiinflammatory Responses and Alleviates Experimental Arthritis

Objective Treg cells modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor II ( TNFRII ) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD 4+ Treg cells. The purpose of the present study was to investigate the therapeutic activity of a novel TNFRII agonist in experimental arthritis as well as the role of different Treg cell subsets. Methods A novel mouse TNFRII –selective fusion protein ( EHD 2‐sc‐ mTNF R 2 ) was generated by genetic engineering. Mouse T cells were incubated together with interleukin‐2 and/or EHD 2‐sc‐ mTNF R 2 , and the effects on Treg cells were analyzed by flow cytometry. Mice with collagen‐induced arthritis ( CIA ) were treated with EHD 2‐sc‐ mTNF R 2 or saline, and the therapeutic effects were monitored and characterized. Results Selective activation of TNFRII was found to expand both CD 4+ and CD 8+ Treg cells. Moreover, TNFRII activation elevated the number of CD 4+ CD 25+ and CD 8+ CD 25+ Treg cells and increased the number of FoxP3‐expressing cells in CD 8+, but not CD 4+, Treg cells, indicating different mechanisms of TNFRII ‐induced expansion of diverse T cell subsets with suppressive activity. In the CIA model, we demonstrated that administration of the TNFRII agonist EHD 2‐sc‐ mTNF R 2 led to the expansion of both CD 4+ and CD 8+ Treg cells in vivo and induced antiinflammatory responses that alleviated arthritis. Conclusion Our findings support the use of TNFRII ‐selective therapeutics as an effective approach to the treatment of arthritic disease and possibly other inflammatory and autoimmune diseases.