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Infection and Immunity, November 2005, p. 7502-7508, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7502-7508.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related Gene Modulates the Response to Candida albicans Infection

Massimiliano Agostini,^2, Elio Cenci,^1, Eva Pericolini,¹ Giuseppe Nocentini,² Giovanni Bistoni,³ Anna Vecchiarelli,^1* and Carlo Riccardi²

Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy,¹ Pharmacology, Toxicology and Chemotherapeutic Section, Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy,² Biological Sciences, Imperial College London, Imperial College Road, London SW7 2AZ, United Kingdom³

Received 20 July 2005/ Returned for modification 2 August 2005/ Accepted 12 August 2005

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.

Editor: A. Casadevall

M.A. and E.C. contributed equally to the paper.

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