IL-10 IS REQUIRED FOR DEVELOPMENT OF PROTECTIVE TH1 RESPONSES IN IL-12-DEFICIENT MICE UPON CANDIDA-ALBICANS INFECTION

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 wer e assessed for susceptibility to C. albicans infections, and for param eters of innate and adaptive immunity. IL-12-deficient mice were highl y susceptible to gastrointestinal infection or to reinfection and show ed 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 immu ne 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 ex ogenous IL-12 or IL-10 impaired IL-4 production and increased resistan ce to infection, through a negative effect on the CTLA-4/B7-2 costimul atory pathway. These results confirm the obligatory role of IL-12 in t he induction of anticandidal Th1 responses, and indicate the existence of a positive regulatory loop between IL-12 and IL-10 that may advers ely affect the innate antifungal response, but is required for optimal costimulation of IL-12-dependent CD4(+)Th1 cells.