GITR (Fc-Fusion)

GITR was identified as a member of the TNF receptor superfamily, by comparing gene expression in untreated and DEX-treated murine T-cell hybridoma. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported.

Interacting protein(s): GITRL
Related products: TNF-Receptor Superfamily

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Description

GITR was identified as a member of the TNF receptor superfamily, by comparing gene expression in untreated and DEX-treated murine T-cell hybridoma. Three alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. The human ortholog was subsequently characterized in human lymphocytes and shown to have limited homology with murine GITR. GITR is expressed at a low level in naïve T cells, but it expresses constitutively in T regulatory cells (Treg).

Upon activation, GITR exhibits a delayed up-regulation in naïve T cells, Treg, and effector T cells (Teff), similar to that of OX40 and 4-1BB, suggesting the GITR-GITRL axis does not play a predominant role in early T cell response, rather exerts its effects at later time point. Like most TNFR family members, human GITRL binds GITR in a trimeric fashion while the mouse ligand-receptor interaction is thought to be dimeric. While initially GITR was thought to exert inhibitory effect on Treg, and a stimulatory effect on Teff, it is now clear that both Treg and Teff are stimulated with the Teff is no longer sensitive to the suppressing effect of Treg.

Similarly, GITR-GITRL interaction was shown to have both inhibitory and stimulatory effects on NK cells. The dual-effect of GITR-GITRL interaction has implications for safety and efficacy of approaches to exploit this axis as a therapeutic target for oncology.

Amino Acid Sequence.

References

1. Tian J, Zhang B, Rui K, Wang S. The Role of GITR/GITRL Interaction in Autoimmune Diseases. Front Immunol. 2020;11:588682. Epub 20201009. doi: 10.3389/fimmu.2020.588682. PubMed PMID: 33163004; PubMed Central PMCID: PMC7581784.

2. Nocentini G, Giunchi L, Ronchetti S, Krausz LT, Bartoli A, Moraca R, Migliorati G, Riccardi C. (1997) A new member of the tumor necrosis factor/nerve growth factor receptor family inhibits T cell receptor-induced apoptosis. Proc Natl Acad Sci U S A. 94:6216-6221

3. Chattopadhyay K, Ramagopal UA, Brenowitz M, Nathenson SG, Almo SC. (2008) Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily. Proc Natl Acad Sci U S A. 105:635-40

4. Zhou Z, Tone Y, Song X, Furuuchi K, Lear JD, Waldmann H, Tone M, Greene MI, Murali R. (2008) Structural basis for ligand-mediated mouse GITR activation. Proc Natl Acad Sci U S A. 105:641-645. 

5. Barao I. (2013) The TNF receptor-ligands 4-1BB-4-1BBL and GITR-GITRL in NK cell responses. Front Immunol. 3:402.