Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. [5] [6] GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1. [7] [8]
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. [8] 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. [9]
GITR interacts with its ligand (GITRL) that is expressed on antigen-presenting cells (APC) and endothelial cells. [9]
Human activation-inducible tumor necrosis factor receptor (AITR) and its ligand, AITRL, are important costimulatory molecules in the pathogenesis of autoimmune diseases. Despite the importance of these costimulatory molecules in autoimmune disease, their role in the autoimmune reaction to herniated disc fragments has yet to be explored. [10]
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. [5]
GITR is co-stimulatory surface receptor for T cells and after interaction with GITRL maintain T cell activation, proliferation, cytokine production, and rescue T cells from anti-CD3-induced apoptosis. GITR can be used as Treg marker and its signaling abrogates the suppressive function of regulatory T cells. Also, GITR plays role in Treg development, as it is expressed already at CD4+CD25+Foxp3- Treg progenitors. [9] [11] [12] [13] [14]
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. [13] [15] [11] [14]
GITR does not have any enzymatic activity and signaling is propagated via recruiting TRAF-family members, specifically TRAF1, TRAF2 and TRAF5, to the GITR-signaling complex. The signaling is then mediated through NF-kB and MAPK pathways. There is an evidence that GITR has unique role for CD8+ and CD4+ T cells. GITR signaling lowers the threshold for CD28 signaling on CD8+ T cells or induces expression of CD137 on CD8+ memory T cells. For CD4+ regulatory T cells, GITR signaling promotes their expansion, inhibits Treg suppressive capacity and promotes resistance of effector T cells to Treg suppression. [11] [16]
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. [9] [12] [11] [16]
GITR-/- mice in pancreatitis model have reduced IkBα and decreased expression of NF-kB p65 protein in pancreatic tissue, and also increased pro-apoptotic markers (e.g. Bax) and decreased anti-apoptotic markers (e.g. Bcl-2). [11] [17]
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. [11] [18] [19] [20]
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. [21] [11]
Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.
Tumor necrosis factor is an adipokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain.
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.
CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.
Tumor necrosis factor receptor type 1-associated DEATH domain protein is a protein that in humans is encoded by the TRADD gene.
CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.
Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα).
Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.
TNF receptor-associated factor 5 is a protein that in humans is encoded by the TRAF5 gene.
TNF receptor-associated factor (TRAF3) is a protein that in humans is encoded by the TRAF3 gene.
LIGHT, also known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily. It is recognized by herpesvirus entry mediator (HVEM), as well as decoy receptor 3.
Tumor necrosis factor ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK) is a protein that in humans is encoded by the TNFSF12 gene.
Death receptor 3 (DR3), also known as tumor necrosis factor receptor superfamily member 25 (TNFRSF25), is a cell surface receptor of the tumor necrosis factor receptor superfamily which mediates apoptotic signalling and differentiation. Its only known TNFSF ligand is TNF-like protein 1A (TL1A).
Apoptosis regulatory protein Siva is a protein that in humans is encoded by the SIVA1 gene. This gene encodes a protein with an important role in the apoptotic pathway induced by the CD27 antigen, a member of the tumor necrosis factor receptor (TFNR) superfamily. The CD27 antigen cytoplasmic tail binds to the N-terminus of this protein. Two alternatively spliced transcript variants encoding distinct proteins have been described.
Tumor necrosis factor receptor superfamily member 12A also known as the TWEAK receptor (TWEAKR) is a protein that in humans is encoded by the TNFRSF12A gene.
Tumor necrosis factor ligand superfamily member 18 is a protein that in humans is encoded by the TNFSF18 gene.
Death receptor 6 (DR6), also known as tumor necrosis factor receptor superfamily member 21 (TNFRSF21), is a cell surface receptor of the tumor necrosis factor receptor superfamily which activates the JNK and NF-κB pathways. It is mostly expressed in the thymus, spleen and white blood cells. The Gene for DR6 is 78,450 bases long and is found on the 6th chromosome. This is transcribed into a 655 amino acid chain weighing 71.8 kDa. Post transcriptional modifications of this protein include glycosylation on the asparagines at the 82, 141, 252, 257, 278, and 289 amino acid locations.
In molecular biology, TACI-CRD2 represents the second cysteine-rich protein domain found in the TACI family of proteins. Members of this family are predominantly found in tumour necrosis factor receptor superfamily, member 13b (TACI), and are required for binding to the ligands APRIL and BAFF. TACI-CRD2 stands for Transmembrane Activator and CAML Interactor- Cysteine Rich Domain 2.
Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. However, some cancers can protect themselves from attack by stimulating immune checkpoint targets.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
