title: IL-10 is required for development of protective Th1 responses in IL-12-deficient mice upon Candida albicans infection.
abstract: IL-12 is both required and prognostic for Th1 development in mice with Candida albicans infection. To delineate further the physiologic role of IL-12 in antifungal immunity, mice deficient for this cytokine were assessed for susceptibility to C. albicans infections, and for parameters of innate and adaptive immunity. IL-12-deficient mice were highly susceptible to gastrointestinal infection or to reinfection and showed elevated production of Candida-specific IgE and IL-4 and defective production of IFN-gamma. The failure to mount protective Th1 responses occurred despite the presence of an unimpaired innate antifungal immune response, which correlated with unaltered IFN-gamma production, but defective production of, and responsiveness to, inhibitory IL-10. IL-10 or IL-12 neutralization increased the innate antifungal resistance in wild-type mice. However, in IL-12-deficient mice, treatment with exogenous IL-12 or IL-10 impaired IL-4 production and increased resistance to infection, through a negative effect on the CTLA-4/B7-2 costimulatory pathway. These results confirm the obligatory role of IL-12 in the induction of anticandidal Th1 responses, and indicate the existence of a positive regulatory loop between IL-12 and IL-10 that may adversely affect the innate antifungal response, but is required for optimal costimulation of IL-12-dependent CD4+ Th1 cells.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Mencacci
authors.forename: E
authors.initials: E
authors.lastname: Cenci
authors.forename: G
authors.initials: G
authors.lastname: Del Sero
authors.forename: C
authors.initials: C
authors.lastname: Fé d'Ostiani
authors.forename: P
authors.initials: P
authors.lastname: Mosci
authors.forename: G
authors.initials: G
authors.lastname: Trinchieri
authors.forename: L
authors.initials: L
authors.lastname: Adorini
authors.forename: L
authors.initials: L
authors.lastname: Romani
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology; D000943:Antigens, Differentiation / Q000502:physiology; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control; D005260:Female; D020022:Genetic Predisposition to Disease / Q000276:immunology / Q000382:microbiology; D007113:Immunity, Innate; D018796:Immunoconjugates; D016753:Interleukin-10 / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D018664:Interleukin-12 / Q000172:deficiency* / Q000235:genetics*; D015847:Interleukin-4 / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010586:Phagocytes / Q000276:immunology / Q000382:microbiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D060908:CTLA-4 Antigen; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D000069594:Abatacept