Distinct functions for CD8 T cells in cutaneous leishmaniasis

PROJECT SUMMARY Cutaneous leishmaniasis is a disease caused by leishmania parasites, and exhibits a wide range of clinical manifestations from self-healing lesions to chronic debilitating infections. Currently there are no vaccines for this disease, and the drugs used to resolve the infections are often ineffective. Although the parasites are important determinants of disease severity, the immune response itself causes a large amount of pathology. CD8 T cells have been shown to play a dual role in disease by being both protective when they produce IFN-γ, but pathogenic when they mediate inflammation-inducing cell death in lesions. We found that IFN-γ-producing protective CD8 T cells are restricted to draining lymph nodes, whereas cytotoxic and therefore pathogenic CD8 T cells are found in leishmanial lesions in both experimental murine models of the disease and in patients. Our preliminary results suggest that this dichotomy in CD8 T cell function is a response to the tissue microenvironment and that protective IFN-γ-producing CD8 T cells become cytolytic once they enter leishmanial lesions. The factors involved in this conversion are unknown, and here we propose to fill this gap in knowledge. In our first aim we will determine how the tissue microenvironment initiates the cytolytic pathway in CD8 T cells. We will test the role of hypoxia, IL-1β and IL-15 in promoting cytolytic T cell development and determine how heterogeneous the CD8 T cells are within the lymph nodes and lesions. In our second aim, we will determine what induces the expression of Blimp-1, a transcription factor that regulates cytolytic T cell function and is required for CD8 T cell-mediated disease. In addition, we will test the ability of Blimp-1 to promote pathology by enhancing CD8 T cell recruitment to lesions. Both of these aims will provide information helpful in designing therapies that might block the development of pathogenic CD8 T cells. Finally, in the third aim we will evaluate the role of neutrophils and the skin microbiota in altering the skin microenvironment. Our preliminary results suggest that neutrophils regulate O2 levels in lesions, that the microbiota amplify neutrophil recruitment and both neutrophils and the microbiota are required for CD8 T cell-mediated disease. Overall, these studies will provide information from murine models that will be foundational in understanding the immune responses mediating and regulating disease in cutaneous leishmaniasis.