A major focus of our research is directed towards understanding the processes that cause aberrant T cell function and T cell-mediated autoimmune diseases exemplified by conditions such as rheumatoid arthritis, inflammatory bowel disease and diabetes. Under normal conditions, developing T cells in the thymus are educated not to attack the body’s own tissues in a process known as T cell tolerance. T cell tolerance is exerted through two different mechanisms: a) elimination of mature, self-reactive T cells in the thymus (central tolerance); b) intrathymic generation of regulatory T cells which in peripheral tissues suppress the activity of self-reactive T cells that escape destruction in the thymus (peripheral tolerance). Establishment of both central and peripheral tolerance occurs in the thymus and is highly dependent on reciprocal interactions between developing T cells and the thymic epithelium, specifically medullary thymic epithelial cells (mTECs). Disruption of these interactions leads to aberrant elimination of autoreactive T cell clones, defective peripheral tolerance and autoimmunity, manifested as T cell-containing inflammatory infiltrates in and autoantibody production against peripheral tissues. We are currently using different mouse models with mutations that disrupt the development of mTECs to understand how disruption of thymic cross-talk between the medullary epithelium and T cells affects T cell development and autoimmunity.
Another focus area of research in the laboratory concentrates on elucidating the cellular and molecular mechanisms that regulate leukocyte migration under homeostatic conditions or during the establishment of an inflammatory response. In these studies we are using mutant mice lacking expression of novel signaling proteins we characterized to study how these proteins regulate leukocyte adhesion and migration in response to chemokines during chronic inflammation. Our studies using mouse models coupled with molecular and biochemical approaches serve as a platform towards elucidating basic aspects of leukocyte biology and are aimed towards identifying novel therapeutic targets to control the behavior of these cells in inflammation and autoimmunity. Read more.