Our long standing interest in cutaneous dendritic cell physiology continues. Recently developed mice that are constitutively, or that can be made conditionally, Langerhans cell-deficient allow definitive studies of Langerhans cell function and development to be carried out for the first time. Using one of these strains of mice and a variety of monoclonal antibodies have allowed us to conclusively identify at least 3 distinct subsets of dendritic cells in skin and to begin to characterize lineage relationships between them. In addition, we have utilized Langerhans cell-deficient to identify an unexpected role for these cells in antibody forming responses. Immunization of transgenic mice at a time when they are Langerhans cell deficient via gene gun leads to selective attenuation of the IgG1 isotype response. Since IgG1 formation is thought to be IL-4-dependent, this suggests that Langerhans cells may be specialized to present antigen to Th2 cells. How this might occur remains to be determined. These findings are described in a paper that was published in the Proceedings of the National Academy of Sciences in 2009. In future studies we will use altternative immunization strategies to discern mechanisms that allow Langerhnas cells to regulate responses to topically applied protein antigens. The above studies have provided data that has resulted in development of new hypotheses regarding Langerhans cell ontogeny. We are in the process of examining the possibility that locally secreted influences that may be keratinocyte-derived may be important regulators of Langerhans cell differentiation. Both in vitro and in vivo approaches are being utilized. Results obtained via these studies implicate Wnt-sinaling in Langerhans cell develpoment. Relavant findings have been published in the Journal Of Investigative Dermatology in 2011. Collaborative studies of dendritic cells and their products in experimental cutaneous leishmaniasis are also ongoing, and results continue to inform our understanding of dendritic cell function in this murine model of an important human disease. Recent results implicate the cytokine IL-17 and neutrophils in Leishmania pathogenesis in susceptible mice. It is anticipated that these insights will promote development of a vaccine that will attenuate the burden of this world-wide health problem. A publication describing these findings was published in the Journal of Immunology in 2009. In additional collaborative studies, the ability of recombinant Leishmania proteins containing the TAT protein transduction domain to serve as vaccine candidates in murine experimental cutaneous leishmaniasis has been tested. These studies indicates the ability to prime CD8 T cells correlates with disease protection and/or attenuation, and the findings was published in the Journal of Investigative Dermatology in 2010. Follow up studies utilizing IL-1 receptor- and IL-1 receptor antagonist (IL-1RA)-deficient mice have additionally characterized the involvement of these entities in the experimental cutaneous leishmaniasis in mice. These resultes were published in manuscripts appearing in Experimental Dermatology and the Journal of Investigative Dermatology in 2011. Two additional collaborations have been productive in FY 2011. The first interaction involved Dr. Robert Seder and his group in NIAID in studies of vaccine optimization. We contributed general expertise regarding dendritic cell physiology as these investigators characterized immune responses to TLF7/8 agonist-protein antigen conjugates. The results of these experiemnts were published in the Journal of Clinical Investigation in 2011. The final collaboration is more substantial and involves of Dr. Maria Morasso and her investigative group in NIAMS. Dr. Morasso has developed a novel mouse in which the transcription factor Dlx3 is selectively deleted in keratinocytes. This results in a barrier defect, production of a variety of chemokines and inflammatory mediators by keratinocyes and subsequent development of a systemic inflammatory syndrome that is characterized by prominent IL-17 production. We are playing a major role in the characterization of the inflammation that occurs in these mice. The initial description of the phenotype of these has now appeared in the Proceedings of the National Academy of Sciences (in 2011) and additional studies are ongoing.
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