Chronic Inflammation Increases the Sensitivity of Mouse Treg for TNFR2 Costimulation

Abstract

TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. In vitro, TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported in vitro expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. In vivo application of TNCscTNF80-induced mild myelopoiesis in naïve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naïve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naïve mice can lead to immune suppression in vivo. These findings support the important role of TNFR2 for Treg cells in immune regulation.

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

“…In contrast, we did not observe TNFRII-dependent changes in IL-2 signaling pathways (i.e., pSTAT-5, p70SK6, and pERK-1/2 levels). This is consistent with recent reports showing that TNFRII activation does not affect pSTAT-5 levels (17,45). Further studies are needed to clarify the molecular effects of TNFRII on CD4+ and CD8+ Treg cells.…”

“…Both M2‐polarized macrophages and Treg cells have been associated with arthritis recovery . While we cannot exclude a contribution of macrophages to the therapeutic effect of EHD2‐sc‐mTNF R2 , a recent study showed that TNFRII signaling in Treg cells induces secretion of IL‐10 , indicating a therapeutic role of Treg cells.…”

Critical Role of Tumor Necrosis Factor Signaling in Mesenchymal Stem Cell-Based Therapy for Autoimmune and Inflammatory Diseases

“…TNFR2 has been identified as a marker for activated Tregs. TNFR2 and its ligands can activate and stabilize Tregs in an inflammatory environment ( 92 – 94 ). A subset of Tregs with high TNFR2 expression exhibits maximally suppressive activities in both mouse and human, which makes them the most desirable cells for the treatment of autoimmune and inflammatory diseases ( 95 , 96 ).…”

A New Venue of TNF Targeting

“…costimulation [355]. Efficient TNFR2 activation requires oligomerization of TNFR2 by membrane-bound TNF.…”