TNFRSF18

Detailed Information

The TNFRSF18 gene is located on human chromosome 1p36.3, comprises at least five exons, and produces three alternatively spliced transcript variants that encode distinct protein isoforms; the predominant isoform is a 241-amino-acid type I transmembrane receptor known as GITR (Glucocorticoid-Induced TNFR-Related protein), also designated CD357 or AITR. Structurally, GITR contains two extracellular cysteine-rich domains (CRDs) that form the molecular basis for ligand engagement, a 24–residue hydrophobic transmembrane segment, and an intracellular tail that lacks intrinsic kinase activity but includes conserved TRAF-binding motifs such as the TNFRSF signature sequence "PVQET." Notably, the cytoplasmic domain harbors a serine phosphorylation site at Ser184, a target of PKCθ whose phosphorylation potentiates downstream signaling. GITR is N-glycosylated at Asn40, a modification that increases its apparent molecular weight and is important for receptor stability and cell-surface localization.

Expression Pattern and Structural Determinants of Ligand Binding

GITR expression is both cell-type specific and activation dependent: it is constitutively high on CD4⁺CD25⁺ regulatory T cells (Treg) (positive in the majority of cells) but low on naïve T cells, whereas effector T cells (Teff) rapidly upregulate GITR following TCR stimulation (often rising several-fold within 24 hours). Expression is also detected on NK cells, macrophages, dendritic cells, and endothelial cells, consistent with a broad immunoregulatory role. The CRD2 region (approximately residues 60–100) mediates binding to the ligand GITRL (TNFSF18); residue-level mutagenesis implicates Tyr68, Phe75, and Arg80 as key contributors to the ligand-receptor interface. GITR exists as a trimer on the cell surface and, upon binding to the homotrimeric GITRL, undergoes conformational changes that expose intracellular TRAF docking sites and initiate downstream signaling.

Biological Functions and Immune Regulatory Mechanisms

GITR operates as a bidirectional modulator of T-cell immunity: it augments effector responses while attenuating Treg suppressive function. In effector T cells, GITR engagement activates NF-κB and MAPK cascades (ERK, JNK, p38), upregulates anti-apoptotic proteins such as Bcl-xL and c-FLIP, promotes proliferation (often a 2–3× increase in proliferation indices) and enhances secretion of cytokines including IL-2 and IFN-γ. In contrast, GITR signaling in Treg reduces expression of the lineage transcription factor FoxP3 (with reported decreases of 30–50%), lowers production of suppressive cytokines such as TGF-β and IL-10, and disrupts stable Treg–DC contacts, thereby weakening suppressive activity. Mechanistically, ligand-induced receptor trimerization recruits TRAF family adaptors in a stepwise manner—initial recruitment of TRAF2/TRAF5 to the PVQET motif forms a primary complex that branches into both classical NF-κB (via IKKβ-mediated IκBα phosphorylation) and non-classical NF-κB (via NIK-dependent p100 processing) pathways. Cell-type specific adaptor expression biases pathway usage: Teff favor MAPK activation while Treg preferentially engage PI3K–Akt signaling. GITR and TCR signals are highly synergistic; co-stimulation markedly amplifies NF-κB transcriptional activity, a process linked to PKCθ-mediated phosphorylation events that coordinate CARMA1 and TRAF2 signaling nodes. During thymic development, GITR–GITRL interactions on thymic epithelial cells contribute to positive selection of CD4⁺CD25⁺FoxP3⁺ Treg, a critical step for establishing central tolerance.

Pathological Roles and Disease Associations

Dysregulated GITR biology is implicated in autoimmunity, cancer immune escape, vascular and bone disorders. Transgenic overexpression of GITR or excessive GITR signaling in animal models compromises Treg function and drives effector T-cell hyperactivation, producing autoimmune phenotypes such as arthritis and thyroiditis; in human rheumatoid arthritis, synovial T cells exhibit markedly higher GITR levels than peripheral blood counterparts and GITR expression correlates with disease activity. In the tumor microenvironment, tumor-infiltrating Treg express elevated GITR levels relative to peripheral Treg, and sustained exposure to GITRL—frequently supplied by tumor-associated macrophages and DCs—strengthens Treg suppression and contributes to CD8⁺ T-cell dysfunction. Beyond immunity, GITR influences non-immune biology: genetic variants and functional perturbations have been linked to disorders of bone metabolism, where loss of GITR reduces osteoclast numbers and bone resorption, producing altered bone density phenotypes.

Figure 1. The TNFR superfamily receptor types, the exon structures of the GITR and GITRL genes, and the major effects of GITR/GITRL signaling on different immune cells and tumorigenic activity. (Papadakos SP, et al., 2024)

Clinical Translation and Therapeutic Applications

The GITR axis has yielded multiple translational approaches. Agonistic anti-GITR antibodies (for example TRX518, MK-4166) aim to simultaneously boost Teff and NK cell activity and blunt Treg suppression; clinical-stage studies report acceptable safety and occasional disease stabilization, and combination regimens with PD-1 blockade show synergistic antitumor activity in preclinical models. Recombinant trimeric GITRL-Fc constructs are in preclinical development to mimic physiological ligand geometry and potently activate GITR. Conversely, antagonists or decoy receptors (e.g., hGITR-Fc) are explored for autoimmune indications and graft-versus-host disease, where blockade of GITR–GITRL reduces pathological T-cell activation. Translational strategies must balance immune activation against the risk of autoimmunity; localized delivery approaches, conditionally activatable prodrugs, and engineered formats that limit systemic exposure are active areas of development. In oncology, combinations with checkpoint inhibitors, bispecific modalities and intratumoral mRNA delivery of GITR agonists are being evaluated to widen therapeutic windows while mitigating systemic toxicity.

Research Challenges and Future Directions

Key challenges remain in dissecting the cell-type specific logic of GITR signaling: the molecular determinants that convert the same receptor engagement into opposite functional outcomes in Treg versus Teff are not fully defined. Emerging data implicate differential expression of phosphatases such as SHP-1 and distinct spatial organization of GITR at immune synapses as factors shaping signal amplitude and quality. The role of GITR in CD8⁺ memory formation and metabolic reprogramming is another open question—GITR deficiency reduces long-term survival of antigen-specific CD8⁺ T cells in infection models, suggesting involvement in memory homeostasis, possibly via effects on lipid metabolism. Future work integrating single-cell multi-omics, spatial transcriptomics, and intravital imaging should clarify the temporal and spatial dynamics of GITR-dependent signalosomes across immune niches. Translationally, predictive biomarkers are needed to stratify responders and guide combination regimens. Overall, GITR remains a promising but complex immunomodulatory node whose therapeutic exploitation requires precise control of context, dose, and delivery.