GITR (glucocorticoid-induced tumor necrosis factor receptor; also named AITR) is a member of the co‑stimulatory subset of the TNF receptor superfamily (1, 2). In mouse, the GITR gene is composed of five exons and encodes multiple length isoforms that arise from alternate splicing. The “standard”, or first reported isoform is a type I transmembrane protein, 228 amino acids (aa) in length that contains a 19 aa signal sequence, a 134 aa extracellular region, a 21 aa transmembrane segment, and a 54 aa cytoplasmic domain. The extracellular region contains four potential N-linked glycosylation sites plus three cysteine-rich pseudorepeats of about 40 aa each (3, 4). The extracellular regions of mouse and human are 57% aa identical. The cytoplasmic domain has a P-x-Q/E-E motif that is known to associate with TRAF2. This is a common characteristic of TNFRSF members with co‑stimulatory functions (4). Three other mouse GITR isoforms (B, C and D) have been reported (5). All share the same N-terminal 101 of 134 aa in the extracellular region (including pseudorepeats #1, #2 and one-half of #3). Isoform D diverges at aa #101 and continues for another 12 aa for a total length of 113 aa. This is a naturally-occurring soluble form. Isoforms B and C show splicing in their cytoplasmic tails that creates cytoplasmic domains of 118 aa and 46 aa, respectively. In both the B and C isoforms, the TRAF2 binding site is spliced out, with a p56lck binding site inserted in isoform B (4). Given its membership in the TNFRSF, it likely functions as a trimer on the cell surface (2). GITR is predominantly expressed on CD4+CD25+ regulatory T cells (Treg) and naïve CD8+ and CD4+ CD25- T cells, where its expression is up-regulated after antigen-driven activation. GITR activation provides co‑stimulatory signals for activated CD4+ CD25- T cells to enhance cell proliferation and augment cytokine production (IL-2, IL-4, IFN-gamma ). On CD4+ CD25+ Treg cells, GITR activation provides co‑stimulatory signals to induce proliferation, setting Treg cells in an active/hyperproliferactive state (6‑8).
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