Genetic Dissection of Primary and Secondary Responses to a Widespread Natural Pathogen of the Gut,Eimeria vermiformis

ABSTRACTBecause most pathogens initially challenge the body at epithelial surfaces, it is important to dissect the mechanisms that underlie T-cell responses to infected epithelial cells in vivo. The coccidian parasites of the genusEimeriaare protozoan gut pathogens that elicit a potent, protective immune response in a wide range of host species. CD4+ αβ T cells and gamma interferon (IFN-γ) are centrally implicated in the primary immunoprotective response. To define any additional requirements for the primary response and to develop a comparison between the primary and the secondary response, we have studiedEimeriainfections of a broad range of genetically altered mice. We find that a full-strength primary response depends on β2-microglobulin (class I major histocompatibility complex [MHC] and class II MHC and on IFN-γ and interleukin-6 (IL-6) but not on TAP1, perforin, IL-4, Fas ligand, or inducible nitric oxide synthetase. Indeed, MHC class II-deficient and IFN-γ-deficient mice are as susceptible to primary infection as mice deficient in all αβ T cells. Strikingly, the requirements for a highly effective αβ-T-cell-driven memory response are less stringent, requiring neither IFN-γ nor IL-6 nor class I MHC. The class II MHC dependence was also reduced, with adoptively transferable immunity developing in MHC class II−/−mice. Besides the improved depiction of an immune response to a natural gut pathogen, the finding that effective memory can be elicited in the absence of primary effector responses appears to create latitude in the design of vaccine strategies.