Our Science – Udey Website
Mark C. Udey, M.D., Ph.D.
Langerhans cells belong to a family of cells that exhibits similar dendritic morphologies and functional activities. These immature epidermal dendritic cells are responsible for the initiation and propagation of immune responses directed towards antigens encountered in skin. Because they can ingest and process complex antigens, Langerhans cells are well situated to function as sentinels at interfaces between organism and environment. After antigen capture, Langerhans cells migrate from skin to regional lymph nodes where, as mature dendritic cells, they initiate and shape primary immune responses in naive T cells. Thus, Langerhans cells (and other dendritic cells) represent cellular bridges between innate and adaptive immune responses. Several lines of evidence suggest that, in different contexts, Langerhans cells may have immune potentiating as well as immune suppressing activities.
Two major initiatives are currently ongoing in the laboratory. One involves characterizing functions of EpCAM (Epithelial Cell Adhesion Molecule; CD326) and the related molecule TROP2. These proteins are expressed by mouse and human Langerhans cells, respectively, as well as selected epithelia and epithelial malignancies. Intercellular adhesion and signaling activities have been ascribed to both EpCAM and TROP2, but details of how they regulate normal cellular physiology remain to be worked out. Both proteins have also been implicated in cancer pathogenesis, and EpCAM has been targeted via immunotherapy approaches in cancer patients.
We are exploring the degree to which, and how, EpCAM regulates Langerhans cell function using conditional knockout mice that we have generated. These mice allow us to selectively and efficiently deplete EpCAM expression in tissues (cells) that are of particular interest. We have determined that EpCAM expression by Langerhans cells promotes Langerhans cell motility within epidermis and Langerhans cell emigration from epidermis after activation. We have also shown that this has functional consequences. We are testing the hypothesis that EpCAM expression facilitates antigen uptake by Langerhans cells by modulating the function of tight junctions that exist between Langerhans cell dendrites (projections) and surrounding keratinocytes.
Our interest in EpCAM and tight junctions arose from studies of EpCAM function in human colon cancer cell lines. We elected to study intestinal epithelial cells because mutations in EpCAM are known to cause congenital tufting enteropathy, a severe diarrheal syndrome characterized by epithelial dysplasia, in humans. After determining that claudin-7 co-immunoprecipitated with EpCAM, we demonstrated that EpCAM stabilizes claudin-7 and claudin-1 by preventing lysosomal degradation. We also demonstrated that association of claudin-1 with EpCAM was dependent on claudin-7, and that claudin-7 and claudin-1 associated with each other in the absence of EpCAM. Inhibition of EpCAM expression in human colon cancer cell lines causes redistribution of selected claudins and changes tight junction properties. These effects are dependent on claudin-7 and claudin-1 expression. In ongoing studies, we are elucidating mechanisms by which EpCAM regulates claudin degradation. We are also interested in determining whether all, or only some, functions of EpCAM are mediated via claudins.
A second major initiative is a collaborative effort with Dr. Maria Morasso (NIAMS) and her coworkers in which we are characterizing the severe skin inflammation that develops in mice whose keratinocytes selectively lack the transcription factor Dlx3. Inflammation in these mice shares features with human psoriasis, with predominant IL-17 production and neutrophil accumulation. We are elucidating mechanisms that link loss of a single autonomously functioning protein in keratinocytes to a complicated inflammatory phenotype with cutaneous and systemic components.
This page was last updated on 1/27/2014.