The laboratory is focused on elucidating important aspects of Langerhans cell biology, particularly those that relate to Langerhans cell differentiation, trafficking, activation and function. Many of these studies utilize Langerhans cell-like cells that we have expanded from murine fetal skin and extensively characterized. We are continuing to study a strain specific polymorphism in dendritic cell IL-1 production and are trying to determine how this polymorphism regulates helper T cell function in C57BL/6 and BALB/c mice. Experiments performed to date indicate that IL-1 may have an unanticipated ability to attenuate murine Th2 cell development. Studies of matrix metalloproteinase production and function in Langerhans cell-like dendritic cells are also in progress. Murine dendritic cells clearly can produce several matrix metalloproteases after stimulation in vitro and in vivo. Defining precise roles for individual enzymes is challenging because gene family members have overlapping substrate specificities. An in vitro assay involving chemokine-dependent invasion of dendritic cells into model basement membranes indicates that this process is matrix metalloproteinase dependent, implicating these enzymes in dendritic cell migration in vivo. Mice with targeted mutations in individual matrix metalloproteinase genes are being studied in an attempt to definitively implicate one, or more, enzymes in dendritic cell biology. Representational difference analysis and array technology have been used to identify known and novel genes that appear to be preferentially expressed in dendritic cells. Confirmation and cataloging of the genes that are differentially represented continues. Several genes that are good candidates for further study have been identified and these are being actively pursued. Initial work will focus on genes that encode proteins whose function(s) can be surmised from structural studies, but that are not already known to play roles in dendritic cell biology. Because traditional gene transduction approaches are only marginally successful in dendritic cells, we are exploring the potential utility of HIV-TAT fusion protein methodology as an alternative means of introducing gene products of interest (and their derivatives) into cells.
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