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* Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy; and
Bioceros BV 3584 CM Utrecht, The Netherlands
The ability of regulatory T (Treg) cells to inhibit aspects of innate and adaptive immunity is central to their protective function in fungal infections. In murine candidiasis, CD4+CD25+ Treg cells prevent excessive inflammation but enable fungal persistence in the gastrointestinal tract, which underlies the onset of durable antifungal protection. In this study, we show that fungal growth, inflammatory immunity, and tolerance to the fungus were all controlled by the coordinate activation of naturally occurring Treg cells, which limited early inflammation at the sites of infection, and pathogen-induced Treg cells (that regulated the expression of adaptive Th immunity in secondary lymphoid organs). Naturally occurring Treg cells required the TRIF pathway for migration to inflamed sites, where the MyD88 pathway would then restrain their suppressive function. Subsequent inflammatory Th1-type immunity was modulated by induced Treg cells, which required the TRIF pathway as well, and acted through activation of IDO in dendritic cells and Th17 cell antagonism. In vitro, using naive CD4+ cells from TRIF-deficient mice, tryptophan metabolites were capable of inducing the Foxp3-encoding gene transcriptionally and suppressing the gene encoding ROR
t, Th17 lineage specification factor. This is the first study to show that the same tryptophan catabolites can foster dendritic cell-supported generation of Foxp3+ cells and mediate, at the same time, inhibition of RORt-expressing T cells.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Research Project on Acquired Immunodeficiency Syndrome (AIDS) Contract No. 30G.28, Italy, and the Specific Targeted Research Project No. LSHM-CT-2005 (Contract No. 005223 (FP6)).
2 Address correspondence and reprint requests to Dr. Luigina Romani, Microbiology Section, Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Via del Giochetto, Perugia, Italy. E-mail address: lromani{at}unipg.it
3 Abbreviations used in this paper: Treg cells, Regulatory T cells; nTreg, naturally-occurring Treg cells; iTreg cells, induced Treg cells; PMN, polymorphonuclear neutrophil; DC, dendritic cell; MLN, mesenteric lymph node; GITR, glucocorticoid-induced TNFR; WT, wild type.
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