Glucocorticoid-Induced Tumour Necrosis Factor Receptor-Related Protein: A Key Marker of Functional Regulatory T Cells
Table 2
Original studies considering GITR as a Treg marker in humans. Studies published in the last three years (2012–2014) were identified from a PubMed database search.
Disease area
Specific disease
Treg phenotype
Comment
Reference
Autoimmune/allergic diseases
Rheumatic diseases
CD4+CD25+
Increased GITR expression in CD4+CD25+ cells from peripheral blood of patients with severe rheumatoid arthritis
About 35% of Tregs is GITR+ in peripheral blood of rheumatoid arthritis and osteoarthritis patients; in the same patients, about 46% of Tregs is GITR+ in synovial membranes
A significant decrease of GITR+ cells, GITR mean fluorescence intensity, and GITR mRNA expression within the Treg population was observed in type 1 diabetes patients compared with healthy controls
Studying the modulation of immune system development in new born, the mRNA expression of FoxP3, GITR, and LAG3 was used to assess Treg expansion in cord blood
Studying the effect of autologous hematopoietic stem cell transplantation in multiple sclerosis patients, GITR and CTLA-4 were used as markers of Treg activity
Hepatocellular, cervical, colorectal, and ovarian carcinoma
Not applicable
Expression of CD25, FoxP3, CTLA-4, and GITR was higher in CD4+Tim-3+ than in CD4+Tim− cells infiltrating tumors; moreover, most CD4+Tim-3+ cells isolated from the paired nontumor tissues and peripheral blood did not express CD25, FoxP3, CTLA-4, and GITR
In human immunodeficiency virus- (HIV-) infected patients with high immune activation and low-level CD4 T-cell repopulation under suppressive high active antiretroviral therapy, Tregs show enrichment in CTLA-4 and GITR markers, compared with the HIV controls and healthy subjects
The expression of CTLA-4 and GITR is decreased in T cells from PBMC of human T-lymphotropic virus-1 associated myelopathy/tropical spastic paraparesis patients as compared to healthy donors
Among all samples with high GITR expression, 77% were human papilloma virus positive; among samples negative for intraepithelial lesion and malignancy, only 33% had high GITR expression
Significantly higher expression of CTLA-4, PD-1, GITR, CD95, CD103, and CD73 on Tregs was detected in the hepatitis E virus infected patients as compared to healthy donors
Epstein-Barr virus infected cord blood dendritic cells drive Tregs development by inducing the expression of FoxP3 and CTLA-4, decreasing the expression of GITR, and promoting the generation of intracellular IL-2 and IL-10
Human herpes virus 6 (HHV-6) infection induces both CD4+ and CD8+ HHV-6-specific Tregs; these HHV-6-specific Tregs have potent suppressive activity and express high levels of CD25, FoxP3, and GITR
The frequency of CD25highGITR+ Tregs is similar in the peripheral blood of chronic dermal leishmaniasis patients and asymptomatically infected individuals
The expression of CTLA-4, GITR, LAG-3, and IL-10 was significantly higher in Treg from filarial-infected patients compared with that in healthy controls
CD4+CD25−CD127+ effector T cells from human peripheral blood can convert into T cells with regulatory activity while concomitantly secreting IFNγ. Upon short-term culture in vitro these cells expressed a panel of common Treg markers, including FoxP3, CD25, GITR, HLA-DR, and CTLA-4
FoxP3+ T cells were differentiated from CD4+CD25− T cells (iFoxP3+ T cells); GITR and CTLA-4 resulted as the only Treg markers at higher levels in iFoxP3+ than in iFoxP3− T cells
miR-126 silencing reduces the expression of FoxP3 on Tregs, which is accompanied by decreased expression of CTLA-4 and GITR, as well as IL-10 and TGF-β, and impairs its suppressive function
PIM1 kinase phosphorylates FoxP3 at serine 422 to negatively regulate its activity; knockdown of Pim1 in in vitro expanded human Tregs promotes FoxP3-induced target gene expression, including CD25, CTLA-4, and GITR, weakens FoxP3-suppressed IL-2 gene expression and enhances the immunosuppressive activity of Tregs