The laboratory is focused on elucidating important aspects of Langerhans cell and dendritic cell biology, particularly those that relate to Langerhans cell/dendritic cell differentiation, trafficking, activation and function. Part of the laboaratory's efforts are directed towards identifying genes that are selectively expressed in dendritic cells and that play important roles in dendritic cell function. To that end, we have generated a cDNA library that is enriched in Langerhans cell/dendritic cell derived sequences and are in the process of characterizing the cDNAs that it contains. We have selected several genes for additional studies because we think that they encode proteins that are of particular interest. One encodes a protein (MFG-E8) that may target antigens on apoptotic cells or cell fragments for ingestion by dendritic cells and cross presentation to CD8 T cells, or to macrophages for clearance. Another encodes a Langerhans cell specific C-type lectin (Langerin). Current and future in vitro and in vivo experiments are intended to determine how proteins encoded by these genes influence dendritic cell function. The ultimate goal of these studies is to develop a more complete understanding of Langerhans cell/dendritic cell biology that will facilitate development of novel therapies that will benefit patients with infectious, inflammatory and/or neoplastic diseases. The laboratory is also actively engaged in studies of the potential utility of HIV TAT protein transduction domain (PTD)-containing proteins in studies of dendritic cell physiology or as antigens that can serve as a basis for dendritic cell-based vaccines. We have determined that PTD-containing recombinant protein antigens can efficiently transduce murine dendritic cells, are metabolized and presented to CD8 T cells as if they had been synthesized endogenously and that PTD-antigen transduced dendrtitic cells can vaccinate mice against tumor engraftment using a xenogenic model tumor antigen. We have also determined that this approach can be used to break tolerance to a murine melanocyte-restricted self antigen (tyrosinase-related protein 2; Trp-2) and that the Trp-2-specific cytotoxic T lymphocytes can eradicate murine melanoma. Studies designed to optimize this vaccine approach in mice are in progress. This methodolgy has potential utility in patients as a component of dendritic cell vaccination strategies because it is highly likely that murine and human dendritic cells will metabolize PTD-containing antigens in the same way and to the same extent.
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