Toll-like receptor 2 suppresses immunity against Candida albicans through induction of IL-10 and regulatory T cells.
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-1alpha, and IL-1beta 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.
Department of Medicine,, University Medical Center St. Radboud, Nijmegen, The Netherlands.
Mihai G
MG
Netea
Roger
R
Sutmuller
Corinna
C
Hermann
Chantal A A
CA
Van der Graaf
Jos W M
JW
Van der Meer
Johan H
JH
van Krieken
Thomas
T
Hartung
Gosse
G
Adema
Bart Jan
BJ
Kullberg
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D002176:Candida albicans / Q000254:growth & development / Q000276:immunology*; D002177:Candidiasis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D002465:Cell Movement / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007111:Immunity, Cellular / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000276:immunology; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000382:microbiology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D016753:Interleukin-10; D007371:Interferon-gamma