Leprosy, a human disease caused by the intracellular pathogen Mycobacterium leprae (mLEP), offers an attractive model for investigating immune responses to infection as the disease represents a spectrum, in which the clinical manifestations correlate with the immune response to the pathogen. By investigating leprosy, we discovered a novel pathway involving NOD2-mediated induction of IL-32, triggering the differentiation of monocytes into CD1+ DC with professional antigen presenting cell function. Although either IL-32 or GM-CSF derived DC efficiently take up, process and present exogenous antigen via MHC class II to CD4+ T cells, only IL-32 derived DC "cross-present" exogenous antigen via MHC class I to CD8+ T cells. Typically, MHC class I samples antigen in the cytoplasm, which in professional antigen presenting cells leads to activation of na?ve CD8+ T cells to become cytotoxic cells, required for host defense against infection. Therefore, "cross- presentation" is required to induce CD8+ cytotoxic T cell responses when antigen is located in the endocytic pathway of antigen presenting cells, i.e. when a pathogen resides in the endocytic pathway or antigen is acquired exogenously. We hypothesize that CD8+ T cells recognize mLEP antigens as a result of IL-32 induced cross-presentation, triggering an antimicrobial response in leprosy. We propose to: 1) elucidate the mechanism(s) by which IL-32 induces cross-presentation of mLEP antigen to CD8+ T cells;2) determine the mechanism of antigen presentation by which CD8+ T cells recognize mLEP infected monocytes/macrophages including the role of the vitamin D antimicrobial pathway in cross-presentation;and, 3) understand the mechanisms by which MHC class I-restricted CD8+ T cells contribute to host defense in leprosy. The studies we propose are intended to provide a comprehensive analysis of cross-presentation and induction of CD8+ T cells to gain insight into mechanisms of host defense against microbial pathogens that reside in the endocytic pathway. We would hope that the insights gained will identify new biomarkers for diagnosis, as well as targets for treatment of chronic human infectious diseases.
We have chosen to study leprosy, because it remains a global health burden on developing countries, because it provides an extraordinary model to study human immune responses to a microbial pathogen and because the lesions are readily accessible for study of immune processes at the site of disease. The investigation of how T cells are activated in leprosy and how they contribute to host defense against the bacteria that causes leprosy will provide new insights into the human immune system as well as provide novel targets for therapeutic intervention against a wide range of infectious diseases.
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