Yang-Xin Fu, M.D., Ph.D.

Molecular Mechanisms Underlying Lymphoid Microenvironment Formation and Immune Response, and its Role in Vaccination, Autoimmunity, and Tumor Immunity

Research Summary

We are interested in defining the essential components of the lymphoid microenvironment required for the development and function of the immune system. Using a comprehensive system of knockout mice and receptor fusion proteins, we have found that lymphotoxin (LT) and TNF are essential for immune cell migrations and formation of lymphoid structures. In addition, our recent work indicates that ligands for LT receptor are essential for the generation and migration of autoreactive T cells. We are currently extending our research areas into other LT/TNF family members.

The next phase of my research plan will focus upon the following aims:

1. The role of LT, LIGHT, and TNF in the development of microenvironment for systemic immune responses. LT-deficient mice have impaired total IgA, IgE, and altered anti-specific IgG responses. We are dissecting various mechanisms by which LT control various Ig production. We are 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. We 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, we will study the signal pathway of core LT family members.
2. The modulation of immune response by newly discovered TNF family members. We have recently cloned and expressed the several TNF family members that may promote or inhibit autoimmune diseases. Using transgenic mice and receptor fusion proteins, we have found that some of members play important role in both central and peripheral tolerance. We are 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. Our recent study indicates that naïve and activated CD4 and CD8+ cells may differentially respond to TNF family ligands. We are studying the mechanisms behind the observation.
3. The role of lymphoid tissues in the immune responses. We 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 immune responses.
4. The role of agonistic antibodies and TNF superfamily receptor fusion proteins in the development of immunity and autoimmunity. Unexpectedly, we have found that agonistic antibodies to TNFSF members can promote tumor immunity but block the development of autoimmune diseases. We are 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.

Selected Papers

Wang J, Lo JC, Foster A, Yu P, Chen HM, Wang Y and Fu YX. (2001). The regulation of T cell homeostasis and autoimmunity by T cell derived LIGHT. J. Clin. Invest. 108:1771-80.

Rennert PD, Hochman PS, Flavell RA, Chaplin DD, Jayaraman S, Browning JL and Fu Y-X. (2001). Essential role of lymph nodes in cellular immunity revealed in Lymphotoxin-a-deficient mice. J. Exp. Med 193:1227:38.

Wu Q, Salomon B, Chen M, Wang Y, Hoffman L, Bluestone JA and Fu Y-X. (2001). Reversal of spontaneous autoimmune insulitis in NOD mice by soluble lymphotoxin receptor. J. Exp. Med 193:1327-32.

Chin R, Zhou P, Alegre M and Fu Y-X. (2001). Confounding factors complicate conclusions in aly model. Nature Med (letter). 7:1165-66.

Wang J, Chun T, Wu Q, Wang Y, Foster A, Roca K, Chen M, Tamada T, Chen L, Wang C-R and Fu Y-X. (2001). The critical role of LIGHT, a TNF family member, in negative selection of thymocytes. J. Immunol. 167:5099-5105.

Sun Y, Wu Q, Lin X, Chen M, Hoffman L, Chen L, Fu YX. (2002). Signaling of 4-1BB Leads to Amelioration of Experimental Autoimmune Encephalomyelitis (EAE). J. Immunol. 168:1457-65.

Hyung-Sik Kang, Robert Chin, Yang Wang, Ping Yu, Jun Wang, Ken Newell, and Yang-Xin Fu. (2002). Signaling via LT?R on stromal cells in the gut is required for IgA production. Nature Immunol. 3:578-586.

Fu YX and Storb U. (2002).  Unexpected site for the generation of autoreactive B lymphocytes. Science 297:2006-8.

Spiotto MT, Yu P, Rowley D, Nishimura M, Meredith SC, Gajeski T, Fu YX and Schreiber H. (2002). Increasing tumor antigen expression ignorance to solid tumors via cross presentation by the tumor stroma. Immunity. 17:737-47.

Sun Y, Chen HM, Subudhi SK, Chen J, Chen L, Fu YX. (2002). Costimulatory molecular-targeted antibody therapy of a spontaneous autoimmune disease. Nature Medicine. 8:1404-13, (see news & views)

Yu P, Spiotto MT, Lee Y, Schreiber H, Fu YX. (2003). Complementary role of CD4+ T cells and secondary lymphoid tissues for cross-presentation of tumor antigen to CD8+ T cells. J. Exp. Med. 197:985-995.

Lo L, Chin R, Lee Y, Kang HS, Wang Y, Weinstock J, Franzoso G and Fu YX. (2003). Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues. J. Clin. Invest. 112: 1495-505.

Prinz M, Heikenwalder M, Junt T, Schwarz P, Glatzel M, Heppner FL, Fu YX, Lipp M and Aguzzi A. (2003). The distance between follicular dendritic cells and nerves controls prion neuroinvasion. Nature. 425:957-962.

Lo L, Chin R, Lee Y, Kang HS, Wang Y, Weinstock J, Franzoso G and Fu YX. (2003). Differential regulation of CCL21 in lymphoid/nonlymphoid tissues for effectively attracting T cells to peripheral tissues. J. Clin. Invest. 112: 1495-505 (see highlight in JCI).

Kang HS, Blink S, Chin R, Lee Y, Kim O, Weinstock J, Waldschmidt T, Conrad D, Chen B, Solway J, Sperling AI and Fu YX. (2004). Lymphotoxin Is Required for Maintaining Physiological Levels of Serum IgE That Minimizes Th1-mediated Airway Inflammation. J. Exp. Med. 198:1643-52.

Lian RH, Chin RK, Nemeth HE, Libby SL, Fu YX and Kumar V. (2004). A role for lymphotoxin in the acquisition of Ly49 receptors during NK cell development V Eur. J. Immunol., 34: 2699ˆ2707.

Wu Q, Fu YX, Sontheimer RD. (2004). Blockade of lymphotoxin signaling inhibits the clinical expression of murine graft-versus-host skin disease. J Immunol. 172(3):1630-6.

Yu P, Lee Y, Liu W, Chin R, Wang J, Wang Y, Schietinger A, Schreiber H and Fu YX. (2004). Priming and expansion of naïve T cells inside tumors lead to the rejection of established tumors at local and distal sites. Nature Immunology. 5:141-49, (see news and views in Nat. Immunol., highlight in Nature Review Cancer, special comment by New England Journal of Medicine).

Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, Wang Y, Fu YX. (2004). Lymphotoxin pathway directs AIRE-mediated negative selection. Nature Immunology. 4:1121-7, (Highlight in Science)

Subudhi SK, Zhou P, Yerian LM, Chin RK, Lo JC, Anders RA, Sun Y, Chen L, Wang Y, Alegre M, Fu YX. (2004). Local expression of B7-H1 promotes organ-specific autoimmunity and transplant rejection. J. Clin. Invest. 113:694-700 (see highlight in JCI and Nature Review Immunology).

Wang J, Anders B, Wu Q, Peng D, Cho JH, Sun Y, Karaliukas R, Hyung-Sik Kang H-S, Turner J, Fu Y-X. (2004). Dysregulated LIGHT expression on T cells mediates intestinal inflammation and contributes to IgA nephropathy. J. Clin. Invest. 113:826-35.

Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H and Fu YX. Intra-tumor depletion of CD4+ cells unmasks tumor immunogenicity leading to rejection of established tumor. J. Exp. Med. in press.

Wang Y, Subudhi SK, Anders RA, Lo J, Wang J, Mink K and Degrandi D, Pfeffer K and Fu YX. Herpes Viral Entry Mediator (HVEM) Is Required for Negatively Regulating T Cell Responses. J. Clin. Invest. in press.