TNFRSF18

GITR is constitutively expressed on CD25+CD4+ regulatory T cells and its expression is upregulated on all T cell subsets after activation. GITR is also expressed on murine neutrophils and NK cells. == Structure ==

GITR is a member of TNFR superfamily and shares high homology in cytoplasmic domain, characterized with cysteine pseudo-repeats, with other members of TNFRSF, such as CD137, OX40 or CD27. == Function ==

GITR interacts with its ligand (GITRL) that is expressed on antigen-presenting cells (APC) and endothelial cells. GITR GITR was identified as a new member of the TNF receptor superfamily, by comparing gene expression in untreated and DEX-treated murine T-cell lines. GITR-/- mice has no developmental problem and are fertile. They have complete block in anti-CD3-induced T cell activation and decrease in regulatory T cells progenitors. After infection challenge, GTIR-/- mice developed less inflammation than WT littermates. == Clinical significance ==

GITR is in high interest as one of the immune checkpoint molecules that have potential in cancer treatment. GITR signaling can promote antitumor and anti-infective immune response, but also can be a driver of autoimmune diseases. Different response to GITR signaling rely on the GITR expression on different immune cell types. How GITR signaling is modulated in the different cells remains unknown. GITR agonistic antibodies are in the clinical trials as activators of effector CD8 T cells, while decreasing number of circulating suppressive regulatory T cells. Limited response to GITR agonistic antibodies is enhanced in combination with anti-PD-1 or anti-CTLA-4 therapies. Atherosclerosis Atherosclerosis is autoinflammatory disease that belongs to the group of cardiovascular diseases (CVD). In atherosclerosis progression, plaques with modified low density lipoprotein (LDL) are formed. GITR expression was detected in plaques macrophages and T cells. Moreover, soluble GITR (sGITR) was present in patient's plasma. GITR potentially might be used as a biomarker of CVD patients, as its plaque expression and levels in plasma can distinguish the CVD patients from healthy controls. == Animal models ==

Asthma model: GITR activation drives an infiltration of eosinophils to the lungs and induces production of cytokines. Model of arthritis: GITR activation increase numbers of Th17 cells in secondary lymphoid organs and stimulate cytokine production. Model of atopic dermatitis: GITR-GITRL pathway activation supports the production of attractants of regulatory T cells (CCL17 and CCL27) and promotes production of Th2-induced cytokines. Inhibition of GITR-GITRL pathway potentially may decrease a severity of different diseases, as asthma, arthritis or atopic dermatitis. ==References==