Fischer R, Proske M, Duffey M, Stangl H, Martinez GF, Peters N, Kraske A, Straub RH, Bethea JR, Kontermann RE, Pfizenmaier K.
Regulatory T cells (Tregs) modulate immune responses and can suppress the development of autoimmune diseases. Tumor necrosis factor receptor 2 (TNFR2) has been recognized as a key receptor on these cells that facilitates expansion and stabilization of CD4 + Tregs. Here, we investigated the therapeutic activity of a novel TNFR2 agonist in experimental arthritis and the role of different Treg subsets.
A novel mouse TNFR2-selective fusion protein (EHD2-sc-mTNF R 2 ) was generated by genetic engineering. Mouse T cells were incubated together with IL-2 and/or EHD2-sc-mTNF R 2 and effects on Tregs were analyzed by flow cytometry. Then mice with collagen induced arthritis were treated with EHD2-sc-mTNF R 2 or saline and therapeutic effect was monitored and characterized.
Selective activation of TNFR2 does expand both, CD4 + as well as CD8 + Tregs. Moreover, TNFR2 activation elevated the number of CD4 + CD25 + Tregs, but not CD8 + CD25 + Tregs, and increased the number of FoxP3-expressing cells in CD8 + Tregs, but not CD4 + Tregs, implying different mechanisms of TNFR2-induced expansion of diverse T cell subsets with suppressive activity. Using the collagen induced arthritis model, we demonstrate that administration of the TNFR2 agonist EHD2-sc-mTNF R 2 leads to the expansion of both CD4 + and CD8 + Tregs in vivo and induces anti-inflammatory responses that alleviate arthritis.
Summarizing, our data argue for the use of TNFR2-selective therapeutics as an effective approach in treating arthritic disease and possibly other inflammatory and autoimmune diseases. This article is protected by copyright. All rights reserved.