Leishmaniasis and many other parasitic diseases remain a major cause of world-wide morbidity and mortality. A central regulatory event in the defense against parasitic diseases is the post-thymic maturational fate of CD4+ (helper) T cells. Murine infection with Leishmania major has a well-defined sequence of cellular events. These features make it a versatile model to study the molecular regulation of CD4+ T cells in vivo. First, the parasite invades mammalian macrophages. Class II- restricted helper T cells become activated and expand after the presentation of parasite antigens. The maturing helper T cells assume one of two developmental fates. The Th1 fate results in control of infection while the Th2 fate results in disseminated disease. Resolution of infection involves elimination of the parasite as well as the host's own formerly-useful immune cells. This proposal will systematically define the molecular events regulating the activated life and death of CD4+ T cells during murine infection with L. major. The proposal has three specific aims. The experimental methods rely on in vivo infection of normal and mutant mice and are complemented by in vitro cellular and molecular analyses of macrophages and T cells.
The first aim will provide a detailed assessment of MHC class II-restricted antigen presentation in macrophages. The influence which antigen presentation has on T cell function during infection will be examined. Additionally, the interactive functions of two MHC class II cofactors, invariant chain and DM, will be assessed by infection of mice deficient in these molecules.
The second aim examines the regulation of helper T cell lineage commitment by defining the cytokine and non-cytokine factors which influence maturational fate and, thus, disease outcome. In addition, a novel hypothesis regarding the molecular basis for T helper subset commitment will be tested using murine leishmaniasis as model system.
The third aim will analyze the homeostatic elimination of parasite-specific T cells which is necessary to avert the potentially pathological consequences of an immune reaction. Cell death molecules which are responsible for killing CD4+ T cells during leishmaniasis will be identified by analysis of loss-of-function mutations. The results of these studies should provide important regulatory information about the control of helper T cells during an immune response. Since many infectious and autoimmune conditions are mediated by the heterogeneous life and death of CD4+ T cells, this should ultimately result in improved treatment for diseases.
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