TNFRSF18

TNFRSF18, also known as GITR (glucocorticoid-induced TNFR-related protein), is a member of the tumor necrosis factor receptor (TNFR) superfamily. The TNFRSF18 gene encodes the GITR receptor, a type I transmembrane protein. The extracellular region contains cysteine-rich domains typical of TNFR family members, and the intracellular tail binds adaptor proteins to activate signaling.

GITR is expressed on regulatory T cells at high levels and is upregulated on conventional T cells upon activation; expression has also been reported on other immune cells in certain contexts. Its ligand, GITRL (TNFSF18), is predominantly expressed by antigen-presenting cells such as dendritic cells, macrophages, and B cells, as well as endothelium in some tissues.

Ligand binding to GITR delivers costimulatory signals that promote T cell proliferation, survival, and cytokine production. In regulatory T cells, GITR signaling can diminish suppressive function, thereby shifting the balance toward an activated effector response. The signaling pathway involves recruitment of TNF receptor–associated factors (TRAFs), leading to activation of NF-κB and MAPK pathways.

Clinical relevance: Owing to its role in T cell activation and regulatory T cell biology, TNFRSF18 is investigated as a target in cancer immunotherapy. Approaches include agonistic antibodies or ligand-based agonists to enhance anti-tumor immunity, often in combination with other immunotherapies. The gene and its protein product are also studied in autoimmune disease and transplantation contexts.