Abstract
There is now compelling evidence that TNF receptor type II (TNFR2) is predominantly expressed on CD4+Foxp3+ regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and plays a major role in the expansion and function of Tregs and MDSCs. Consequently, targeting of TNFR2 by either antagonists or agonists may represent a novel strategy in the treatment of cancer and autoimmune diseases, by downregulating or upregulating suppressor cell activity. The advance in the understanding of complex structure of TNFR2 and its binding with TNF at molecular levels offers opportunity for structure-guided drug discovery. This article reviews the current evidences regarding the decisive role of TNFR2 in immunosuppressive function of Tregs and MDSCs, and the current effort to develop novel TNFR2-targeting therapeutic agents in the treatment of cancer, autoimmune diseases, and graft-versus-host disease. To shed light on the potential TNFR2-targeting small molecules, we for the first time performed virtual screening of 400,000 natural compounds against the two TNF-binding sites, regions 3 and 4, of TNFR2. Our result showed that the top hits at region 4 had slightly higher docking energies than those at region 3. Nevertheless, free energy calculation from the TNF–TNFR2 molecular dynamics simulation revealed that the binding strength of TNF in region 3 is only one-tenth of that in region 4. This suggests that region 3 is a potentially more viable binding site to be targeted by small molecules than region 4. Therefore, the effectiveness in targeting region 3 of TNFR2 deserves further investigation.
Highlights
Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine that plays a major role in immune and inflammatory responses through two distinct receptors: TNF receptor type I (TNFR1, known as p55 and TNFRSF1A) and TNF receptor type II (TNFR2, known as p75 and TNFRSF1B)
TNFR1 is ubiquitously expressed on almost all cell types, and TNF–TNFR1 signaling has various functions
TNFR2 is more restrictedly expressed on certain cell types, such as minor subsets of lymphocytes [2, 3], endothelial cells [4], and human mesenchymal stem cells [5]
Summary
Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine that plays a major role in immune and inflammatory responses through two distinct receptors: TNF receptor type I (TNFR1, known as p55 and TNFRSF1A) and TNF receptor type II (TNFR2, known as p75 and TNFRSF1B). In RA patients, anti-TNF therapy drives the expansion of Tregs by enhancing the binding of membrane-bounded TNF (mTNF) expressed by monocytes to TNFR2 [26] Taken together, these studies indicate that TNFR2 is an emerging target to expand functional Tregs for the treatment of autoimmune diseases and GvHD. STAR2 protein, a selective mouse TNF-based agonist of TNFR2, has been shown to expand host-type radiation-resistant Tregs and improve the outcome after allo-HCT, prolong the survival without compromising the anti-leukemia or anti-infective effects in a mouse model of GvHD [11] These findings shed a light on the therapeutic potential of novel TNFR2-targeting agents in the treatment of autoimmune and inflammatory diseases. The enhanced binding is due to the closer contact of the ligand with Asp and
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