Gender-Dependent Innate IL-10 Production as a Key Pathogenic Factor to Promote Toxoplasmic Encephalitis

Reactivation of chronic infection with Toxoplasma gondii in the brains of immunocompromised individuals results in the development of life-threatening toxoplasmic encephalitis (TE). To improve prevention and management of TE, it is important to understand the immunopathogenesis of the disease. Epidemiological studies showed significantly higher incidence of TE in female AIDS patients than male patients. Results from our previous studies in ADIS patients suggest that the pathogenic immune responses predisposing the patients to reactivation of T. gondii infection are involved in the pathogenesis of TE. However, the mechanisms of the pathogenic immune responses that predispose females to developing TE are unknown. Importantly, our preliminary studies uncovered that female mice with the genetic background susceptible to cerebral T. gondii infection are more susceptible to development of TE than males. Our preliminary studies also suggested that IL-10 overly produced by innate immune cells in the brain of the female mice suppresses the protective innate immune responses and skews T cell responses in the brain from the protective Th1-type to suppressive IL-10- dominant profile to facilitate reactivation of T. gondii infection. Based on these observations, the specific aims of this proposal are designed to determine the pathogenic roles of IL-10 produced by each of brain-resident and infiltrating blood-derived innate immune cell populations to down-regulate both protective innate and T cellmediated immunity in the brain and increase susceptibility to reactivation of T. gondii infection in a genderdependent manner. The first aim is focused to elucidate the suppressive activities of the innate IL-10 on the protective innate immunity in the brain to facilitate reactivation of T. gondii infection. We will infect SCID mice with depletion of IL-10 production in the different innate cell populations in the brain and examine the effects of the depletion of the innate IL-10 on cerebral expression of IL-12, IFN-ƒ× and IFN-ƒ×-mediated effector molecules, and tachyzoite growth during reactivation of the infection. We will also determine the identity of the major producer of the pathogenic innate IL-10 in the brain during reactivation of the infection. The second aim is to determine whether the cerebral innate IL-10 alters T cell recruitment and/or development in the brain and induces a shift of T cell cytokine production from IFN-ƒ×- to IL-10-dominant profile to facilitate reactivation of T. gondii infection. We will transfer immune T cells to the infected SCID mice with depletion of IL-10 in the different innate cell populations described in Aim 1, and determine changes in numbers of sub-populations of CD4+ and CD8+ T cells that produce either IFN-ƒ× or IL-10 or both in their brains, expression of IFN-ƒ×-mediated protective effector molecules, and cerebral tachyzoite growth during the course of the infection. These studies will generate the novel and crucial information that allow us to begin understanding the mechanisms of genderdependent, pathogenic immune responses that facilitate reactivation of cerebral T. gondii infection.