Structures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions

• Published in: Nature communications 2021-03, Vol.12 (1), p.1378-1378, Article 1378
• Main Authors: Wang, Feng, Chau, Bryant, West, Sean M., Kimberlin, Christopher R., Cao, Fei, Schwarz, Flavio, Aguilar, Barbara, Han, Minhua, Morishige, Winse, Bee, Christine, Dollinger, Gavin, Rajpal, Arvind, Strop, Pavel
• Format: Article
• Language: English
• Subjects: 14; 631/250/251; 631/45/612/1237; 631/535/1266; 631/80/86; Animals; Anticancer properties; Biophysical Phenomena; CD4 antigen; CD8 antigen; Cell activation; Cell Line; Cell Membrane - metabolism; Cell survival; Glucocorticoid-Induced TNFR-Related Protein - chemistry; Glucocorticoid-Induced TNFR-Related Protein - metabolism; Glucocorticoids; Humanities and Social Sciences; Humans; Immune system; Immunoregulation; Ligands; Lymphocytes; Lymphocytes T; Membrane structures; Membranes; Mice; Models, Molecular; multidisciplinary; Mutation; Protein Binding; Proteins; Receptors; Reproducibility of Results; Science; Science (multidisciplinary); Signaling; Therapeutic targets; Tumor necrosis factor; Tumor necrosis factor-TNF; Tumor Necrosis Factors - chemistry; Tumor Necrosis Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21563-z

Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and GITR ligand (GITRL) are members of the tumor necrosis superfamily that play a role in immune cell signaling, activation, and survival. GITR is a therapeutic target for directly activating effector CD4 and CD8 T cells, or depleting GITR-expressing regulatory T cells (Tregs), thereby promoting anti-tumor immune responses. GITR activation through its native ligand is important for understanding immune signaling, but GITR structure has not been reported. Here we present structures of human and mouse GITR receptors bound to their cognate ligands. Both species share a receptor–ligand interface and receptor–receptor interface; the unique C-terminal receptor–receptor enables higher order structures on the membrane. Human GITR–GITRL has potential to form a hexameric network of membrane complexes, while murine GITR–GITRL complex forms a linear chain due to dimeric interactions. Mutations at the receptor–receptor interface in human GITR reduce cell signaling with in vitro ligand binding assays and minimize higher order membrane structures when bound by fluorescently labeled ligand in cell imaging experiments. Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and GITR ligand (GITRL) regulate immune cell activities, including anti-tumor immune responses. Structures and visualization of human and mouse GITR–GITRL complexes offer insight into the architecture of higher-order membrane assemblies, and their signaling.