Differential regulation of immune responses by highly and weakly virulent Cryptococcus neoformans isolates

Early inflammatory responses, delayed-type hypersensitivity (DTH) responses , and cytokine profiles were studied in mice infected by the pulmonary rout e with either a highly virulent isolate (NU-2) or a weakly virulent isolate (184A) of Cryptococcus neoformans, After infection, NU-2 remained in the l ungs and the capsule became more pronounced during the first 24 h, whereas 184A induced an immediate inflammatory reaction and was rapidly cleared fro m the lungs. Cryptococcal antigen (GXM) appeared in sera early after infect ion with NU-2 and increased over the entire observation period, There was n o detectable GXM in sera from 184A-infected mice. Both C. neoformans isolat es induced anticryptococcal cell-mediated immune responses, but the respons es had different profiles. DTH in NU-2-infected mice appeared at day 15 aft er infection and waned by day 21, whereas DTH in 184A-infected mice was pre sent by day 5 and continued to increase. T helper I (Th1) cytokines (interl eukin 2 [IL-2] and gamma interferon) were made by spleen cells early after infection with either isolate. NU-2-infected mice lost their ability to pro duce these cytokines, but 184A-infected mice retained it. IL-4, a Th2 cytok ine, was not detected in infected mice. The regulatory cytokine IL-10 was m ade by spleen cells early but not later after infection with the highly vir ulent isolate and was not produced by spleen cells from 184A-infected mice. IL-10-deficient mice survived an NU-2 infection significantly longer than wild-type mice, suggesting that IL-10 is important in down-regulating the p rotective immune response. The induction of anergy appears to be responsibl e for the inability of NU-2-infected mice to control a C. neoformans infect ion.