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Current Research

SPECIFICITY AND FUNCTION OF INTRAEPITHELIAL γδ T CELLS
My lab has a long term interest in interactions between intraepithelial γδ T cells and neighboring epithelial cells. We have focused our studies on interactions in the thymus, skin and intestine. We are investigating the development, specificity and function of these γδ T cells. Our results have defined unique properties of these cells and support a specialized role for epithelial γδ T cells in immune surveillance, wound repair, inflammation, and protection from malignancy.

ANTIGENS FOR γδ T CELLS
Close physical interactions between γδ T cells and neighboring epithelial cells suggested the possibility of functional interactions between these two populations. We have demonstrated that skin γδ T cells monitor neighboring keratinocytes for signs of damage or disease. We have isolated the antigen for the skin γδ T cells from damaged keratinocytes. Most αβ T cells recognize peptide antigens derived from foreign proteins and presented by self MHC molecules. In contrast the skin γδ antigen is nonpeptidic and does not require MHC molecules for presentation. Experiments are in progress to further define this novel antigen. The recognition of unique antigens and ability to perform specialized functions supports a novel immunological role for the intraepithelial γδ T cells.

IDENTIFICATION OF CORECEPTORS FOR γδ T CELLS
Skin γδ T cells do not express the coreceptors CD4 or CD8 and do not express the costimulatory receptor CD28. In addition to antigen, we propose that damaged keratinocytes express molecules that participate in skin γδ T cell activation through binding to coreceptors or costimulatory molecules on the T cell surface. Studies are in progress to identify γδ T cell coreceptors and determine the function that they play in skin γδ T cell responses. We have produced monoclonal antibodies that recognize unique molecules expressed on the surface of either keratinocytes or skin γδ T cells that impact interactions between these two cell types, suggesting coreceptor or costimulatory functions. The role of the newly identified molecules will be tested in wound healing and other functional studies.

A ROLE FOR INTRAEPITHELIAL γδ T CELLS IN TISSUE REPAIR
Our previous studies indicated that intraepithelial γδ T cells in the skin and intestine inducibly produce the epithelial growth factor KGF that plays an important role in wound healing. In addition these cells produce a panel of cytokines and chemokines, which may function to recruit inflammatory cells to sites of trauma and modulate the growth and function of neighboring cells. We have proposed that the intraepithelial γδ T cells may play an important role in epithelial homeostasis in normal and disease conditions. To test this hypothesis we have analyzed the role of skin γδ T cells in epidermal wound healing. The γδ T cells are activated at wound sites and produce cytokines including KGFs. In the absence of skin γδ T cells, there are defects in keratinocyte proliferation and tissue reepithelialization following wounding. In addition, we have analyzed the role of intestinal γδ T cells in a murine model of colitis in collaboration with R. Boismenu. We find increased numbers of γδ T cells at sites of inflammation and have evidence that they are activated and producing cytokines and chemokines locally, including KGF. In the absence of γδ T cells there is increased damage and delayed repair of intestinal ulcerations. In patients with Ulcerative Colitis and Crohn's disease we find increased numbers of γδ T cells both in blood and at sites of active disease as well as increased levels of KGF at sites of inflammation. These results validate the animal models and support our hypothesis that intraepithelial γδ T cells respond to tissue damage and play an important role in tissue repair. Our future studies should provide information that will further define the role of γδ T cells in epithelial inflammatory disorders and may be useful in designing new therapies.