Dr. Fu is interested in defining the essential components of the lymphoid microenvironment required for development of autoimmune diabetes. Using a comprehensive system of knockout mice and receptor fusion proteins, he has found that lymphotoxin (LT) and TNF are essential for immune cell migrations and formation of lymphoid structures. In addition, his recent work indicates that ligands for LT receptor are essential for the generation and migration of autoreactive T cells into islets. Dr. Fu is currently extending his research areas into other LT/TNF family members. The role of LT, LIGHT, and TNF in the development of microenvironment for systemic immune responses. He is dissecting various mechanisms by which LT control various Ig production. He is generating transgenic mice that express LT, LIGHT, and TNF on T, B, and dendritic cells. By breeding back to LT, LIGHT, and TNF knockout mice, mice expressing these TNF family ligands only on a specific lineage will be available. The role of subset of LT-producing cells will be further explored. Dr. Fu will further define the role of these LT-expressing cells in the development and function of non-T and non-B cells, including FDC, DC and NK cells. In addition, the role of these cells in various autoimmune diseases will be explored, including experimental autoimmune encephalitis (EAE), autoimmune diabetes, and lupus. Using combination of transgenic and KO mice, Dr. Fu will study the signal pathway of core LT family members. He is exploring novel therapy to block autoreactive T cells into islets or transplanted islets in NOD mice and other mice. The modulation of immune response by newly discovered TNF family members. He has recently cloned and expressed the several TNF family members that may promote or inhibit autoimmune diseases. He is now developing and using various autoimmune diabetes, lupus, and EAE model to study the role of these TNF members in induction and maintenance of autoimmunity. Dr. Fu’s recent study indicates that naïve and activated CD4 and CD8+ cells may differentially respond to TNF family ligands. The role of lymphoid tissues in the immune responses. Dr. Fu can readily generate various congenital lymphoid tissue deficient mice, which can be used as a model to study the role of such lymphoid tissues in autoimmune diabetes. The role of agonistic antibodies and TNF superfamily receptor fusion proteins in the development of immunity and autoimmunity. He has found that an agonistic antibody to 4-1BB, a TNF family member, can block the development of autoimmune diseases. Dr. Fu is investigating the signaling pathways and cell type involved in the inhibition. Receptor fusion protein can be used to study the role functions of various ligands in the different stages of immune response.