TNFSF18

Official Full Name

TNF superfamily member 18

Organism

Homo sapiens

GeneID

8995

Background

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for receptor TNFRSF18/AITR/GITR. It has been shown to modulate T lymphocyte survival in peripheral tissues. This cytokine is also found to be expressed in endothelial cells, and is thought to be important for interaction between T lymphocytes and endothelial cells. [provided by RefSeq, Jul 2008]

Synonyms

TL6; AITRL; GITRL; TNLG2A; hGITRL;

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Detailed Information

The TNFSF18 gene encodes Tumor Necrosis Factor Superfamily Member 18, commonly referred to as Glucocorticoid-Induced TNF Receptor Ligand (GITRL). GITRL is a type II transmembrane protein that primarily exerts its biological activity in the form of soluble trimers, generated either through proteolytic cleavage or vesicular shedding from the cell membrane. Its expression is tightly regulated and constitutively observed on antigen-presenting cells, including dendritic cells, macrophages, and B cells. Additionally, GITRL expression is markedly upregulated on activated T lymphocytes and a key non-immune cell population-endothelial cells-under inflammatory conditions. The only known receptor for GITRL is TNFRSF18 (GITR), which is highly expressed on T lymphocytes, particularly regulatory T cells (Tregs) and activated effector T cells. The specific pattern of ligand and receptor expression provides insights into GITRL's pivotal role at the immunological synapse and vascular interface.

Biological Significance

TNFSF18/GITRL serves as a critical T cell co-stimulatory molecule, profoundly influencing T lymphocyte survival, proliferation, and effector function through interaction with GITR. When GITRL is presented on antigen-presenting cells or endothelial cells and engages GITR on T cells, it delivers a potent co-stimulatory signal that lowers the activation threshold, enhancing T cell receptor-mediated proliferation and cytokine production. Notably, GITR signaling exhibits differential effects across T cell subsets. Engagement of GITR can diminish or even reverse the suppressive function of Tregs, which normally express high levels of GITR, while simultaneously augmenting the responsiveness of effector T cells. This dual effect produces a net increase in immune activation.

Beyond adaptive immunity, GITRL plays a key role in interactions between innate immune cells and endothelial cells. Under inflammatory conditions, GITRL expression on endothelial cells is strongly induced. Engagement of endothelial GITRL with GITR on infiltrating T cells or monocytes activates NF-κB signaling and phosphorylation of Signal Transducer and Activator of Transcription 1 (STAT1). This cascade upregulates adhesion molecules on the endothelial surface, promoting firm leukocyte attachment and subsequent transmigration from the vasculature to inflamed tissues. Thus, the GITRL-GITR axis functions not only as a co-stimulatory signal for T cell activation but also as a hub coordinating immune cell recruitment to sites of inflammation, linking adaptive immune activation with inflammatory responses.

Figure 1. Effects of Glucocorticoid-induced TNFR-related protein (GITR) triggering in effector T cells and Treg cells. (Tian J, et al., 2020)

Clinical Relevance

TNFSF18/GITRL has garnered significant clinical interest as an immunotherapy target in oncology. Its ability to enhance effector T cell activity while attenuating Treg function makes agonistic anti-GITR antibodies an attractive strategy to "release the brakes" and potentiate antitumor immunity. In preclinical models, agonistic anti-GITR antibodies-used alone or in combination with other immune checkpoint inhibitors-have demonstrated robust antitumor activity, promoting T cell infiltration and effective tumor clearance. Several such antibodies have progressed to early-phase clinical trials for advanced solid tumors.

However, clinical development faces challenges, primarily balancing efficacy with safety. Since GITR is broadly expressed on activated effector T cells, systemic administration of potent agonists can provoke excessive immune activation, leading to severe autoimmune-like adverse events or cytokine release syndrome. Careful optimization of dosing regimens and treatment windows is therefore critical.

Conversely, given the role of the GITRL-GITR axis in promoting inflammation and leukocyte extravasation, this pathway may also represent a potential target in autoimmune or inflammatory diseases. In such contexts, antagonistic antibodies or soluble receptors could block GITRL-GITR interactions, suppress pathological T cell activation, and limit immune cell recruitment to affected tissues. These approaches are still in early-stage exploration. Monitoring soluble GITRL levels in patient serum may also serve as a biomarker for disease activity or immune-related adverse events.

In summary, the TNFSF18/GITRL pathway represents a powerful immunoregulatory switch, and precise modulation-whether agonistic or antagonistic-offers promising avenues for cancer therapy and immune-mediated inflammatory diseases, though successful translation requires careful optimization of dose, timing, and combination strategies.

References

Grohmann U, Volpi C, Fallarino F, et al. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nat Med. 2007;13(5):579-586.
Croft M, Siegel RM. Beyond TNF: TNF superfamily cytokines as targets for the treatment of rheumatic diseases. Nat Rev Rheumatol. 2017 Apr;13(4):217-233.
Tian J, Zhang B, Rui K, et al. The Role of GITR/GITRL Interaction in Autoimmune Diseases. Front Immunol. 2020 Oct 9;11:588682.

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