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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:
- 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.
- 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.
- 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.
- 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 Y, Subudhi SK, Anders RA, Lo J, Wang J, Mink K, Degrandi D, Pfeffer K, Fu YX. Herpes Viral Entry Mediator (HVEM) Is Required for Negatively Regulating T Cell Responses. J Clin Invest 115:711-717, 2005.
Yu P, Lee Y, Liu W, Krausz T, Chong A, Schreiber H, Fu YX. Intra-tumor depletion of CD4+ cells unmasks tumor immunogenicity leading to rejection of established tumor. J Exp Med 201:779–791, 2005.
Wang J, Anders RA, Wang Y, Turner JR, Pfeffer K, Fu Y-X. LIGHT mediates Crohn’sd by activation of Th1 cells. J Immunol 174:8173-8182, 2005.
Anders RA, Subudhi SK, Wang J, Pfeffer K, Fu YX. Contribution of the Lymphotoxin β Receptor to Liver Regeneration. J Immunol 175:1295-1300, 2005.
Sun Y, Blink SE, Chen JH, Fu YX. Regulation of Follicular Dendritic Cell Networks by Activated T Cells: The Role of CD137 Signaling. J Immunol 175:884-890, 2005.
Wang Y-G, Kim KD, Wang J, Yu P, Fu YX. Stimulating LTβR on the dendritic cells is critical for their homeostasis and expansion. J Immunol 175:6997-7002, 2005.
Lo JC, James E, Quiambo R, Kinsella MC, Alegre, M, Weih F, Franzoso G, Hoffmann A, Fu YX. Coordination between NF-kB family members p105/p50 and p100/p52 is essential for mediating LTβR signals in the development and organization of secondary lymphoid tissues. Blood 107:1048-1055, 2006.
Fan Z, Yu P, Wang Y, Lee Y, Wang Y, Fu M, Liu W, Sun Y, Fu YX. Natural killer activation by LIGHT triggers tumor specific CD8+ T cell immunity at the tumor site to reject established tumors. Blood 107:1342-1351, 2006.
Youjin Lee, Robert K. Chin, Peter Christiansen, Yonglian Sun, Alexei V. Tumanov, Jing Wang, Alexander Chervonsky, and Yang-Xin Fu. Recruitment and activation of naïve T cells in the islets by lymphotoxin beta receptor dependent tertiary lymphoid structure. Immunity, 25:399-409, 2006.
Zhu M, Chin RK, Christiansen PA, Lo JC, Liu X, Ware C, Siebenlist U, and Fu Y.-X. NF-kappa B2 is required for the establishment of central tolerance through an AIRE-dependent pathway. J. Clin. Invest. 116:2964-71, 2006.
Schwarz RT, Wang F, Shen L, Clayburgh DR. Su L, Wang, Y, Fu, YX, and Turner JR. LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology 132:2383–2394, 2007.
Lo JC, Wang Y, Tumanov AV, Bamji M, Yao Z, Reardon, CA, Getz GS, and Fu YX. Lymphotoxin beta receptor-dependent control of lipid homeostasis.. Science 316:285-288, 2007. (see “LIGHT Hits the Liver” in Perspectives at the same issue of Science, highlight in Nature Review Immunology).
Krieg, C, Boyman, O, Fu, Y. X., Kaye, J. B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation. Nat. Immunol. 8:162-71, 2007.
Zhang, B, Bowerman, N. A, Salama, J. K, Schmidt, H, Spiotto, M. T. Schietinger, A. Yu, P. Fu, Y. X. Weichselbaum, R. R. Rowley, D. A. Kranz, D. M. Schreiber, H. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J. Exp. Med. 204:49-55, 2007.
Fu, J, Xu, D, Liu, Z, Shi, M, Zhao, P, Fu, B, Zhang, Z, Yang, H, Zhang, H, Zhou, C, Yao, J, Jin, L, Wang, H, Yang, Y, Fu, YX, Wang, FS. Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339, 2007.
Kim KD, Zhao J, Auh S, Du P,. Yang, X., Tang H, and Fu YX. Adaptive immune cells temper initial innate responses. Nature Med 13:1248-1252, 2007 (see commentary entitled “Not so fast: adaptive suppression of innate immunity” in Nature Medicine (13: 1142-1144, 2007) and highlight entitled “T cells calm the storm” by Nature Review Immunogy.
Plant SR, Iocca HA Wang, Thrash CY, O’Connor BP, Arnett, HA Fu Y-X, Carson MJ, and Ting P.-Y. Lymphotoxin Receptor (LtR): Dual Roles in Demyelination and Remyelination and Successful Therapeutic Intervention Using LtR–Ig Protein. Journal of Neuroscience, 27(28):7429 –7437, 2007.
Zhu M, Chin, RK., Tumanov AV, Liu X., and Fu YX. Lymphotoxin beta receptor impinges on organ-specific central tolerance in an orchestrated manner. J. of Immuno. 2007, 179: 8069–8075.
Tumanov AV, Christiansen PA, Fu YX.The role of lymphotoxin receptor signaling in diseases. Curr Mol Med. 2007, 7:567-78,
Xu G-L, Liu D, Okwor I, Wang Y, Korner H, Kung S, Fu YX and Uzonna JE. LIGHT is critical for IL-12 production by dendritic cells, CD4+ Th1 cell development and resistance to Leishmania major, J. Immunology 2007, 179: 5358–5366.
Yu P, Lee Y, Wang Y, Christiansen P, Liu X, Gajewski TF, Schreiber H, Wang X, and Fu YX. Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastasis. J. of Immuno. 179: 1960–1968, 2007.
Zhang, B., Zhang, Y., Bowerman, N. A., Schietinger, A., Fu, Y. X., Kranz, D. M., Rowley, D. A., Schreiber, H.. Equilibrium between host and cancer caused by effector T cells killing tumor stroma. Cancer Res 68(5): 1563-71, 2008.
De Trez, C., Schneider, K., Potter, K., Droin, N., Fulton, J., Norris, P. S., Ha, S. W., Fu, YX., Murphy, T., Murphy, K. M., Pfeffer, K., Benedict, C. A., Ware, C. F.The inhibitory HVEM-BTLA pathway counter regulates lymphotoxin receptor signaling to achieve homeostasis of dendritic cells." J Immunol 180(1): 238-48, 2008.
Papa S, Zazzeroni F, Fu YX, Bubici C, Alvarez K, Dean K, Christiansen PA, Anders RA, Franzoso G. Gadd45beta promotes hepatocyte survival during liver regeneration in mice by modulating JNK signaling. J. Clinical Investigation PMC2276398
Zhao J, Kim KD, Yang, X Auh S, Du P, Fu YX and Tang H. Hyper innate responses in neonates lead to increased morbidity and mortality after infection. PNAS, USA. 105: 7528–7533, 2008.
Zhu M, Fu YX. Coordinating development of medullary thymic epithelial cells. Immunity. 29:386-8, 2008.
Yu P, Fu YX. Targeting tumors with LIGHT to generate metastasis-clearing immunity. Cytokine Growth Factor Rev. Jun-Aug;19(3-4):285-94, 2008.
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