TNF and TNF receptor type 2 (TNFR2) have been shown to be important for generation of myeloid-derived suppressor cells (MDSC). In order to analyze whether and how TNFR2 passes the effect of TNF on, myeloid cells from TNFR2-deficient mice were compared to respective cells from wild-type mice. Primary TNFR2-deficient myeloid cells showed reduced production of NO and IL-6 which was attributable to CD11b+ CD11c− Ly6C+ Ly6G− immature monocytic MDSC. TNFR2-deficient MDSC isolated from bone marrow were less suppressive for T cell proliferation compared to WT-derived MDSC. These differences on myeloid cells between the two mouse lines were still observed after co-culture of bone marrow cells from the two mouse lines together during myeloid cell differentiation, which demonstrated that the impaired functional capacity of TNFR2-deficient cells was independent of soluble factors but required membrane expression of TNFR2. Similarly, adoptive transfer of TNFR2-deficient bone marrow cells into wild-type hosts did not rescue the TNFR2-specific phenotype of bone marrow-derived myeloid cells. Therefore, membrane TNFR2 expression determines generation and function of monocytic MDSC.

Tumor necrosis factor (TNF) and its receptors TNF receptor type 1 (TNFR1) and type 2 (TNFR2) have a central role in chronic inflammatory diseases. While TNFR1 mainly confers inflammation, activation of TNFR2 elicits not only pro-inflammatory but also anti-inflammatory effects. In this study, we wanted to investigate the anti-inflammatory therapeutic potential of selective activation of TNFR2 in mice with established collagen-induced arthritis. Mice with established arthritis induced by immunization with bovine collagen type II were treated with six injections of the TNFR2-specific agonist TNCscTNF80, given every second day. Two days after treatment cessation, the cell compositions of bone marrow, spleen and lymph nodes were analyzed. Mice were visually scored until day 30 after the start of therapy and the degree of joint inflammation was determined by histology. Treatment with TNCscTNF80 increased arthritis-induced myelopoiesis. Little effect was seen on the infiltration rate of inflammatory immature myeloid cells and on the reduction of lymphoid cells in secondary lymphoid organs. Upon treatment, frequency of regulatory T (Treg) cells in the CD4 T-cell population was increased in both spleen and inguinal lymph nodes. In addition, the expression of TNFR2 on Treg cells was enhanced. The clinical score started to improve 1 week after cessation treatment and remained lower 30 days after initiation of therapy. The histological score also revealed amelioration of joint inflammation in TNCscTNF80-treated versus control mice. Activation of TNFR2 might provide a suitable therapeutic strategy in autoimmune arthritis by increasing the numbers of regulatory cell types, in particular Treg cells, and by attenuation of arthritis.Cellular and Molecular Immunology advance online publication, 29 January 2018; doi:10.1038/cmi.2017.138.

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.

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