The glucocorticoid-induced tumor necrosis factor receptor-related gene modulates the response to Candida albicans infection.
The glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene (GITR; TNFRSF18) modulates immune response activating coaccessory signals in T cells and is expressed at high levels in CD4+CD25+ cells. Its ligand (GITRL) is expressed in antigen-presenting cells, where it is capable of promoting signaling. We investigated the role of GITR/GITRL interaction during disseminated candidiasis in GITR knockout (GITR-/-) mice. GITR-/- mice survived longer and had a significantly decreased yeast load in kidneys and brain compared to GITR+/+ mice. Since protective immunity to the fungus is mediated by antigen-specific T helper (Th) 1 cells, we studied in vitro cytokine production following infection. CD4+ T cells of GITR-/- mice demonstrated a more efficient Th1 polarization as suggested by a two- to threefold decreased production of interleukin- (IL-)4 and IL-10 and a four- to fivefold increased production of gamma interferon compared to GITR+/+ mice. This effect was not due to differences in lymphocyte and dendritic cell (DC) subpopulations in infected mice as demonstrated by flow cytometric studies. To verify whether DC activity was differently modulated, DCs were cocultured with CD4+ T cells in the presence of heat-inactivated Candida albicans. DCs, cocultured with GITR+/+ CD4+CD25+ cells produced a lower amount of IL-12 than DCs cocultured with GITR-/- CD4+CD25+ T cells. These results suggest that GITR regulates susceptibility to systemic candidiasis by negatively modulating IL-12 production and promoting polarization of CD4+ T cells towards Th2 by analogy with OX40, another TNF receptor superfamily member.
Agostini
Massimiliano
M
Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Cenci
Elio
E
Pericolini
Eva
E
Nocentini
Giuseppe
G
Bistoni
Giovanni
G
Vecchiarelli
Anna
A
Riccardi
Carlo
C
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002177:Candidiasis / Q000235:genetics* / Q000276:immunology* / Q000382:microbiology; D005786:Gene Expression Regulation; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018664:Interleukin-12 / Q000096:biosynthesis / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D016176:T-Lymphocyte Subsets / Q000276:immunology
D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D018664:Interleukin-12