TNFR2 Is Critical for the Stabilization of the CD4+Foxp3+ Regulatory T Cell Phenotype in the Inflammatory Environment

Abstract

Several lines of evidence indicate the instability of CD4+FoxP3+ regulatory T cells (Tregs). We have therefore investigated means of promoting the stability of Tregs. In this study, we found that the proportion of Tregs in mouse strains deficient in TNFR2 or its ligands was reduced in the thymus and peripheral lymphoid tissues, suggesting a potential role of TNFR2 in promoting the sustained expression of FoxP3. We observed that upon in vitro activation with plate-bound anti-CD3 Ab and soluble anti-CD28 Ab, FoxP3 expression by highly purified mouse Tregs was markedly down-regulated. Importantly, TNF partially abrogated this effect of TCR stimulation and stabilized FoxP3 expression. This effect of TNF was blocked by anti-TNFR2 Ab, but not by anti-TNFR1 Ab. Furthermore, TNF was not able to maintain FoxP3 expression by TNFR2-deficient Tregs. In mouse colitis model induced by transfer of naïve CD4 cells into Rag1−/− mice, the disease could be inhibited by co-transfer of WT Tregs, but not by co-transfer of TNFR2-deficient Tregs. Furthermore, in the lamina propria of the colitis model, the majority of WT Tregs maintained FoxP3 expression. In contrast, increased number of TNFR2-deficient Tregs lost FoxP3 expression. Thus, our data clearly show that TNFR2 is critical for the phenotypic and functional stability of Treg in the inflammatory environment. This effect of TNF should be taken into account when designing future therapy of autoimmunity and GVHD by using TNF inhibitors.

Essential protective role of tumor necrosis factor receptor 2 in neurodegeneration

“…Accordingly, TNFR1 antagonists such as ATROSAB should be superior to conventional anti-TNF drugs in the treatment of neurodegenerative diseases, as they spare TNFR2 and even enhance TNFR2 signaling but still block detrimental signals transmitted via TNFR1. In addition to the potential therapeutic use of TNFR1-specific antagonistic antibodies, TNFR2-selective agonists seem to be particularly suitable to treat inflammatory, demyelinating diseases, because next to the direct neuroprotective effects shown in this report, data from different laboratories outline that TNFR2 is also involved in immune suppression via expansion and stabilization of regulatory T cells (41)(42)(43)(44)(45)(46)(47), and induces remyelination (9,13,14). Thus, like TNFR1 antagonists, TNFR2 agonists might promote therapeutic effects via multiple cellular targets.…”

Aminopeptidase P3 (APP3), a novel member of the TNF/TNFR2 signaling complex, induces phosphorylation of JNK

“…In addition, in the MOG 35-55 -induced experimental autoimmune encephalomyelitis (EAE) mouse model of the human demyelinating disease multiple sclerosis, TNFR2 deficiency exacerbates demyelination (Kontoyiannis et al, 1999;Suvannavejh et al, 2000). Furthermore, recent reports suggest that TNFR2 signaling also mediates myocardial protection (Monden et al, 2007;Wang et al, 2008), neuroprotection (Arnett et al, 2001;Fontaine et al, 2002) and activity of regulatory T cells (Treg) (Chen et al, 2007;Chen et al, 2010;Chen et al, 2013). Furthermore, the molecular mechanisms of signal initiation have been revealed through analysis of the X-ray crystal structure of the TNF-TNFR2 signaling complex (Mukai et al, 2010).…”

Generation and Characterization of Small Single Domain Antibodies Inhibiting Human Tumor Necrosis Factor Receptor 1

“…Selective TNFR1 inhibition blocks inflammation by enabling T regs to suppress IL17 production, and it promotes T reg activity via TNFR2 signaling (57,58). Also in CD, murine and human data point to an important role for T regs , the suppressive functions of which are attributed to TNFR2 (59,60). Indeed, in mice T regs are critical for maintaining intestinal tolerance to luminal antigens and for preventing intestinal inflammation (61).…”