Person:

Faustman, Denise

Background: Soluble TNF superfamily (TNFSF) ligands are less stable and less active than their transmembrane (tm) analogues. This is a problem for the therapeutic use of recombinant TNFSF ligands in diverse diseases including cancer and autoimmunity. Creating TNFSF ligand analogues with improved targeting of their respective receptors is important for research and therapeutic purposes. Findings: Covalent internal cross-linking of TNF monomers by double mutations, S95C/G148C, results in stable trimers with improved TNFR2 function. The resulting mutein induced the selective death of autoreactive CD8 T cells in type-1 diabetic patients and demonstrates targeted proliferation and expansion of human CD4 Tregs. Conclusions: Stable TNF trimers, created by internal covalent cross-linking, show improved signaling. The high structural homology within the TNF superfamily provides an opportunity to extend internal cross-linking to other TNF superfamily proteins to produce active trimers with improved stability and receptor signaling, and with potential applications for cancer, autoimmunity, infections, and transplantation. Electronic supplementary material The online version of this article (doi:10.1186/s40591-015-0044-4) contains supplementary material, which is available to authorized users.

The regulatory cytokine tumor necrosis factor (TNF) exerts its effects through two receptors: TNFR1 and TNFR2. Defects in TNFR2 signaling are evident in a variety of autoimmune diseases. One new treatment strategy for autoimmune disease is selective destruction of autoreactive T cells by administration of TNF, TNF inducers, or TNFR2 agonism. A related strategy is to rely on TNFR2 agonism to induce T-regulatory cells (Tregs) that suppress cytotoxic T cells. Targeting TNFR2 as a treatment strategy is likely superior to TNFR1 because of its more limited cellular distribution on T cells, subsets of neurons, and a few other cell types, whereas TNFR1 is expressed throughout the body. This review focuses on TNFR2 expression, structure, and signaling; TNFR2 signaling in autoimmune disease; treatment strategies targeting TNFR2 in autoimmunity; and the potential for TNFR2 to facilitate end organ regeneration.