GITRL

GITRL (glucocorticoid-induced TNF receptor-related protein ligand, TNFSF18) is the type II transmembrane TNF family ligand of the co-stimulatory receptor GITR (TNFRSF18). GITRL is a 177-amino-acid protein forming stable homotrimers, expressed on antigen-presenting cells-dendritic cells, macrophages and B cells-upon activation by TLR ligands or inflammatory stimuli, on endothelial cells, and on tumor cells of diverse origins; unlike most TNF family ligands, mouse GITRL can self-assemble into supramolecular clusters conferring constitutive signaling capacity. GITRL-GITR engagement potentiates effector T-cell and NK-cell proliferation, cytokine secretion, survival and cytotoxicity, destabilizes regulatory T-cell suppressive function, and can break peripheral tolerance, driving autoimmune exacerbation in models of experimental autoimmune encephalomyelitis and colitis. In cancer, GITRL expression by tumors can either foster antitumor immunity or promote immune evasion through preferential Treg expansion; agonistic anti-GITR antibodies are in clinical trials for advanced solid tumors, seeking to reinvigorate exhausted effectors while disabling intratumoral Tregs.