Abstract
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.
Highlights
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in regulating diverse bodily functions including cell growth modulation, inflammation, tumorigenesis, viral replication, septic shock, and autoimmunity [1]
TNFR2 agonism or induction of TNF is an effective means of selectively killing autoreactive CD8+ T cells in animal models, in human cells in vitro [33, 58, 83, 87, 88] and in blood samples taken from patients with type I diabetes [57]
TNFR1 ANTAGONISM Tumor necrosis factor binds to TNFR1 and TNR2
Summary
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in regulating diverse bodily functions including cell growth modulation, inflammation, tumorigenesis, viral replication, septic shock, and autoimmunity [1] These functions hinge upon TNF’s binding to two distinct membrane receptors on target cells: TNFR1 ( known as p55 and TNFRSF1A) and TNFR2 ( known as p75 and TNFRSF1B). One overlapping feature is that various defects in TNF signaling pathways, acting through the TNF receptors and NFkB in autoreactive T cells, occur in both human and mouse models of various autoimmune disorders, including Crohn’s disease, Sjogren’s syndrome, multiple sclerosis, ankylosing spondylitis, and type I diabetes [20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39]. In T cells, activation of TRADD or FADD activates the caspases, resulting in apoptosis (Figure 1)
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