Research Interests: Death receptors, caspase regulation, and gamma delta T cell function in infection and autoimmunity
Dr. Budd’s group examines the role of death receptors, such as Fas (CD95), and their downstream caspases in apoptosis and regulation of the immune response. Fas-deficient humans and mice develop an autoimmune disease resembling lupus, as well as profound enlargement of lymph nodes. Dr. Budd is studying the origin of the lymphocytes that accumulate in the absence of Fas-induced death. His group is also examining the Fas signal pathway and has made the paradoxical discovery that caspase-8 is required not only for cell death by Fas, but also to initiate proliferation of T lymphocytes. The switch between cell death and growth appears to be regulated by the caspase-8 paralogue, c-FLIP. Current studies are focused on determining how and where in a cell caspase activity is controlled during cell growth versus cell death. As caspase-8 and c-FLIP are ubiquitously expressed, they are likely to regulate cell growth and death in many cell types.
Dr. Budd’s group also investigates the function of gamma delta T cells in Lyme arthritis. Lyme Disease is the most common vector-borne disease in the U.S. It is caused by the spirochete, Borrelia burgdorferi, that is transmitted by the tick, Ixodes scapularis. We have observed that an unusual and small subpopulation of T lymphocytes known as gamma delta T cells accumulate in the joint fluid in patients with Lyme arthritis. These gamma delta T cells respond to lipopeptides from B. burgdorferi. Our findings to date suggest a model whereby Borrelia lipopeptides bind to Toll-like receptor 2 on antigen presenting dendritic cells, which then upregulate surface molecules recognized by the gamma delta T cells, such as the MHC-like molecules CD1b and MICA. This results in expression by the gamma delta T cells of very high levels of surface FasL, and intense cytolysis of other neighboring T cells. However, due to high levels of c-FLIP in dendritic cells, they are not only resistant to Fas-induced death, but are activated by Fas ligation.
Last modified November 14 2013 12:41 PM