Dr. Ralph Budd
Death receptor regulation of apoptosis in the immune system
The Fas-deficient lymphoproliferative (lpr) mouse develops an autoimmune disease resembling human lupus, as well as profound enlargement of lymph nodes. We are studying the origin and cause of the lymphocytes that accumulate in the absence of Fas-induced death. In parallel studies, we are examining the alterations in Fas signaling caused by its natural inhibitor, c-FLIP. FLIP-transgenic mice manifest T cell hyperproliferation and a Th 2 cytokine bias. FLIP-Tg mice manifest worse allergic airway disease. We are studying how c-FLIP alters the signaling of T cells by associating with TRAF2 and RIP1 to augment activation of NF-?B, and with Raf-1 to increase ERK activation. We are also investigating the function of ?? 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 ?? T cells accumulate in the joint fluid in patients with Lyme arthritis. These ?? 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 ?? T cells, such as the MHC-like molecules CD1b and MICA. This results in expression by the ?? T cells of very high levels of surface FasL, and intense cytolysis of other neighboring T cells, especially Th2 CD4+ cells. However, due to high levels of cFLIP in dendritic cells, they are not only resistant to Fas-induced death, but are activated by Fas ligation.
Fortner, K.A., and Budd, R.C. The death receptor, CD95 (Fas/APO-1), mediates the deletion of T lymphocytes undergoing homeostatic proliferation. Submitted.
Chen, Y, Kelm, R.J., Budd, R.C., Sobel, B.E., and Schneider, D.J. Inhibition of Apoptosis and Caspase-3 in Vascular Smooth Muscle Cells by Plasminogen Activator Inhibitor Type-1. J. Cell. Biochem. 92:178-188, 2004
Wu, W., Fortner, K.A., Russell, J.Q.,Tschopp, J., and Budd, R.C. CD4+ T cells from c-FLIPL- transgenic mice express increased GATA-3, decreased NF-B and a Th2 cytokine bias J. Immunol. 172:4724-4732, 2004.
McLellan, B.S., Rincon, M., Bushway, P., Flavell, R.A., and Budd, R.C. Elevated NFAT transcriptional activity in lpr mature T cells. Submitted.
Roessner, K., Wolfe, J., Shi, C., Sigal, L.H., Huber, S.A., and Budd, R.C. High Expression of Fas-Ligand by Synovial Fluid-Derived γ δ T cells in Lyme Arthritis J. Immunol. 170:2702-2710, 2003.