Journal of Immunology Research

Review Article

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	[53]
		CD4⁺CD25^+/highCD127^low/−	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	[54]
		CD4⁺CD2GITR⁺	CD4⁺CD2GITR⁺ cell population is expanded in the peripheral blood of SLE patients with inactive disease	[10]
		CD4⁺CD25⁺, CD4⁺CD25^high and CD4⁺CD25⁺CD12	The expression of GITR in Tregs positively correlates with SLE disease activity index (SLEDAI) in SLE patients	[55]
		CD25^+/highCD127^−/lowFoxP3⁺	Decrease in the GITR⁺ Treg/GITR⁺ effector T cell ratio in SLE¹ patients	[56]
		CD4⁺CD25⁻GITR^high	CD4⁺CD25⁻GITR^high cell population is expanded in the peripheral blood of Sjogren’s syndrome patients	[57]
		CD4⁺CD25^lowGITR⁺	CD4⁺CD2GITR⁺ cell population is expanded in the peripheral blood of Sjogren’s syndrome patients with inactive disease	[58]
		Not applicable	Presence of GITR⁺ cells in lymphocytic foci and periductal areas of the labial salivary glands of Sjogren’s syndrome patients	[59]
	Diabetes	CD4⁺CD25^high	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	[60]
	Multiple sclerosis	CD4⁺FoxP3⁺	In multiple sclerosis patients treatment with INFβ increases Treg number as a consequence of GITRL expression in monocytes	[61]
	Atopic diseases	Not applicable	The expression of FoxP3, GITR, and LAG3 was used to assess the effect of IL-10 polymorphisms on Treg number	[62]
	Atopic diseases	Not applicable	The expression of FoxP3, GITR, and LAG3 was used to assess the effect of STAT6 polymorphisms on Treg number	[63]
	Asthma	CD4⁺CD25^highCD127^low	The expression of GITR in Tregs isolated from severe allergic asthma patients was similar to that from mild to moderate asthma	[64]
	Vascular diseases	CD4⁺CD25⁺FoxP3⁺	The mRNA levels of GITR resulted significantly lower in Kawasaki disease patients as compared to healthy controls	[65]
	Vascular diseases	CD4⁺CD25⁺FoxP3⁺	Significant reduction (4-fold) in relative expression of GITR mRNA in immune thrombocytopenic purpura patients as compared to healthy controls ()	[66]
	—	Not applicable	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	[67]

Transplantation		CD4⁺CD25⁺	Studying the expansion of pTreg in allogeneic culture, FoxP3, GITR, and CTLA-4 were used as markers of Treg activity	[68]
		CD4⁺CD25^high	Studying the effect of autologous hematopoietic stem cell transplantation in multiple sclerosis patients, GITR and CTLA-4 were used as markers of Treg activity	[69]
		CD8⁺CD25⁺	Studying iCD8 T cells generated in response to allogeneic dendritic cells, GITR, CTLA-4, and FoxP3 were used as markers of Treg differentiation	[70]

Immunodeficiency		CD4⁺CD25⁺FoxP3⁺	Expression of GITR and CTLA-4 was used as markers of Treg activity	[71]

Cardiomyopathy		GITR⁺	GITR⁺ Tregs are increased in human dilated cardiomyopathy	[72]

Tumors	Leukemia and lymphoma	CD4⁺GITR⁺	CD4⁺GITR⁺ cells are increased in multiple myeloma patients	[73]
		CD4⁺CD25⁺FoxP3⁺	GITR is a marker of in vitro induced Tregs by coculture with multiple myeloma cells	[74]
		CD4⁺GITR⁺	About 50% of CD4⁺ cells infiltrating Hodgkin’s lymphoma are GITR⁺	[75]
		CD4⁺CD25⁺FoxP3⁺	GITR expression is modulated in Tregs from thalidomide-treated patients	[76]
	Breast tumors	CD4⁺CD25^highGITR⁺CD127^−/low and CD4⁺CD25^lowGITR⁺CD127^high	Both Treg subsets are increased in tumor-positive lymph nodes	[77]
	Breast tumors	CD25⁺CD4⁺	Expression of FoxP3, GITR, CTLA-4, and CD103 was tested as markers of Treg activity	[78]
	Colorectal carcinoma	CD4⁺CD25^highFoxP3⁺GITR⁺	CD4⁺CD25^highFoxP3⁺GITR⁺ cell subset is increased 3-fold in the PBMC of patients with colorectal carcinoma	[79]
	Brain tumor	CD4⁺CD25^bright	GITR is one of the markers of Tregs in PBMC	[80]
	Liver cancer	CD4⁺CD25⁺FoxP3⁺	Tumor Tregs express higher levels of GITR than Tregs in tumor-free liver tissue and blood	[81]
	Ovarian cancer	Not applicable	Poorer survival was associated with the minor allele at SNPs in TNFRSF18/TNFRSF4 in patients with mucinous ovarian cancer (rs3753348, P = 9.0 × 10⁻⁴)	[82]
	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	[83]
	Cervical carcinoma	GITR⁺	High GITR expression was observed in both cervical carcinoma and high-grade squamous intraepithelial lesion samples	[84]

Infection	Viral	CD4⁺CD25^highFoxP3⁺	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	[85]
		CD4⁺FoxP3⁺	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	[86]
		GITR⁺	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	[84]
		Not applicable	CTLA-4, GITR, CD103, CD25, CD69, IL-10, and TGF-β1 expression in PBMCs of hepatitis E virus infected patients were significantly elevated	[87]
		CD4⁺CD25⁺FoxP3⁺ and CD4⁺CD25⁻FoxP3⁺	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	[88]
		Not applicable	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	[89]
		Not applicable	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	[90]
	Parasitic	CD25^highGITR⁺	The frequency of CD25^highGITR⁺ Tregs is similar in the peripheral blood of chronic dermal leishmaniasis patients and asymptomatically infected individuals	[91]
		Not applicable	The -163C/T (ss491228440) polymorphism in TNFRSF18 gene is not a susceptibility factor in uncomplicated malaria and parasitaemia in Congolese children	[92]
		FoxP3⁺	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	[93]

In vitro studies		CD4⁺CD25⁺	Emodin treatment of dendritic cells increases the number of Tregs, which express lower levels of HLA-DR, GITR, and CTLA-4	[94]
		CD4⁺FoxP3⁺	All FoxP3⁺ invariant NKT cells display CD25 but not necessarily CTLA-4 or GITR	[95]
		CD25^highCD45RA⁻	CD25^highCD45RA⁻ in vitro induced Tregs (iTregs) express high levels of FoxP3, GITR, and CTLA-4 and low levels of CD127	[96]
		CD4⁺IFNγ⁺	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	[97]
		Not applicable	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	[98]
		CD4⁺FoxP3⁺	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	[99]
		CD4⁺CD25^highFoxP3⁺	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	[100]

CTLA-4: cytotoxic T-lymphocyte antigen 4; FoxP3: forkhead box P3; HLA-DR: human leukocyte antigen DR; IL-10: interleukin-10; IL-2: interleukin-2; LAG-3: lymphocyte-activation gene 3; PBMC: peripheral blood mononuclear cells; PD-1: programmed cell death-1; SLE: systemic lupus erythematosus; TNFRSF18: GITR; TNFRSF4: OX40 (CD134).