GITR (Glucocorticoid-Induced TNFR Family-Related) also termed AITR (Activation-Inducible TNFR Family Receptor) is a member of the TNFRSF18 (TNF Receptor Superfamily 18). It is a 228-amino acids type I transmembrane protein that is suggested to be a close relative of 4-1BB and CD27. Inducible during T-Cell activation, the molecule has a 19 amino acid residue signal sequence, a 134 amino acid residue extracellular region, a 23 amino acid residue transmembrane segment and a 52 amino acid residue cytoplasmic domain. It has three cysteine-rich motifs in its extracellular region. Its ligand is GITRL (AITRL). GITR expression is upregulated on T-Cells. A high level of GITR is constitutively expressed on CD4+ CD25+ regulatory T-Cells. CD4+ GITR+ T-Cells are equivalent to CD4+ CD25+ regulatory T-Cells. GITR plays an important role in the regulation of T-Cell proliferation and TCR-mediated apoptosis. GITR resulted to be expressed in normal T lymphocytes from thymus, spleen, and lymph nodes, although no expression was detected in other nonlymphoid tissues, including brain, kidney, and liver. The GITR gene is induced in T-Cells by DEX (Dexamethasone), as well as by other cell-activating stimuli. GITR, and have implications for the evolution and function of the TNF/NGFR family as well as for the mechanism of control of apoptosis in T-Cells (Ref.1).
GITR is structurally similar to other TNFR superfamily members, such as OX40,
4-1BB and CD27, which lack the intracellular death domain required for induction of apoptosis and mediate intracellular signaling by recruiting TRAFs (TNF Receptor-Associated Factor) proteins to their cytoplasmic tails. These molecules are highly expressed after lymphocyte or T-Cell activation. In addition, like OX40, 4-1BB and CD27, GITR stimulation shows a costimulatory activity for TCR-stimulated naïve resting T-Cells. GITR is distinct from other TNFR family proteins in the role it plays in CD25+ CD4+ T-Cell-mediated suppression, although further study is needed to assess the costimulatory activity of GITR on T-Cells at different activation stages, on T-Cell subsets and on T-Cell effector functions (including cytokine production) (Ref.2). GITR interacts with the pro-apoptotic protein Siva and induces apoptosis. GITR associates with TRAF1 (TNF Receptor-Associated Factor-1), TRAF2 (TNF Receptor-Associated Factor-2), and TRAF3 (TNF Receptor-Associated Factor-3) but not TRAF5 (TNF Receptor-Associated Factor-5) and TRAF6 (TNF Receptor-Associated Factor-6). GITR induces the anti-apoptotic transcription factor NF-KappaB (Nuclear Factor-KappaB), via a pathway that appeared to involve TRAF2 and NIK (NF-KappaB-Inducing Kinase) (Ref.3). Modulation of GITR-mediated signal transduction may break allograft tolerance as well as self-tolerance; alternatively, blockade of GITR-mediated signals may enable CD4+ CD25+ T-Cells to maintain allograft tolerance more stably. Thus, GITR may be a suitable molecular target for preventing or treating autoimmune disease, including tumor immunity, or establishing transplantation tolerance in humans.