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Departments of
*
Medicine,
Tumor Immunology, and
Pathology, University Medical Center St. Radboud, Nijmegen, The Netherlands;
Nijmegen University Center for Infectious Diseases, Nijmegen, The Netherlands; and
¶ Department of Biochemical Pharmacology, University of Konstanz, Konstanz, Germany
Toll-like receptor (TLR) 2 and TLR4 play a pivotal role in recognition of Candida albicans. We demonstrate that TLR2-/- mice are more resistant to disseminated Candida infection, and this is associated with increased chemotaxis and enhanced candidacidal capacity of TLR2-/- macrophages. Although production of the proinflammatory cytokines TNF, IL-1
, and IL-1
is normal, IL-10 release is severely impaired in the TLR2-/- mice. This is accompanied by a 50% decrease in the CD4+CD25+ regulatory T (Treg) cell population in TLR2-/- mice. In vitro studies confirmed that enhanced survival of Treg cells was induced by TLR2 agonists. The deleterious role of Treg cells on the innate immune response during disseminated candidiasis was underscored by the improved resistance to this infection after depletion of Treg cells. In conclusion, C. albicans induces immunosuppression through TLR2-derived signals that mediate increased IL-10 production and survival of Treg cells. This represents a novel mechanism in the pathogenesis of fungal infections.
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