Department of Molecular Genetics, Microbiology and Immunology

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Yufang Shi, PhD

Yufang Shi, Ph.D.
Professor
Office: 732-235-4501
Lab: 732-235-4502
shiyu@umdnj.edu

Office: S.R. 112
Lab: S.R. Bldg.

Publications

Devadas, S. Das, J. Liu, C., Zhang, L., Roberts, A.I., Pan, Z., Moore, P., Das, G., and Shi, Y. 2006 Apoptosis Modulates the Th1/Th2 Balance: Distinct Roles for Caspases and Granzyme B. Immunity, 25:237-47

Das, J, Eynott, P, Jupp, R, Bothwell,, A, Van Kaer, L., Das, G*. and Shi, Y.F*. 2006. Natural killer T cells and CD8+ T cells are dispensable for T cell–dependent allergic airway inflammation. Nature Medicine, 12:1345-1346

Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y.F., Gelinas C, Fan Y, Nelson DA, Jin S, White E. 2006 Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell, 10(1):51-64.

Das, G., Mittal, J. Zhang, YY., Bothwell, A., Van Kare Luc, and Shi, Y.F. 2006. Pivotal Roles of Major Histocompatibility Complex Class Ib Restricted CD8+ T Cells in Autoimmune Diseases J. Exp. Med. 203:2603-11

Shi YF, Liu CH, Roberts AI, Das J, Xu G, Ren G, Zhang Y, Zhang L, Yuan ZR,Tan HS, Das G, Devadas S. 2006. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know. Cell Res. 16:126-33.

Yuan, ZR, Wang, RX, Lou, XY, Zhang, LY and Shi, YF. 2005. Identification and Characterization of a Novel Cell Survival Gene Critical in Apoptosis and Tumorigenesis. Cancer Research, 65: 10716-24

Greeneltch, KM, Kelly-Welch AN, Keegan, A.D. and Shi, Y.F. 2005. Chronic Morphine Administration Promotes Th2 Differentiation via a Fas/FasL-Dependent Mechanism. J. Immunol, 175: 4999-5005

Greeneltch, KM, Haudenschild, C.C., Keegan, A.D., Shi, YF. 2004 The Opioid Antagonist Naltrexone Blocks Acute Endotoxic Shock by Inhibiting Tumor Necrosis Factor-a Production. Brain Behav Immun 18(5):476-84

Sun, EW, Gao, Y., Chen, J.F., Roberts, A.I., Wang, X.N., Chen, Z.H., and Shi, Y.F. 2004 Allograft Tolerance Induced by Donor Apoptotic Lymphocytes Requires Phagocytosis in the Recipient. Cell Death and Differ. 11:1258-1264.

Pestka, S, Krause, C., Sarkar, D., Walter, M., Shi, Y.F., Fisher, P. IL-10, Interferons and Related Class 2 Cytokines and Receptors. Ann. Rev. Immunol. 2004. 22:929-979

Zhang, XR, Zhang, LY, Devadas, S, Li, L, Keegan, AD and Shi, YF. Reciprocal Expression of TRAIL and CD95L in Th1 and Th2 Cells: Role of Apoptosis in T Helper Subset Differentiation. Cell Death Differ2003. 10: 216-224.

Solomon, JC, Sharma, K, Wei, LX, Fujita, T and Shi, YF. 2003. A Novel Role for Sphingolipid Intermediates in Activation- Induced Cell Death in T-cells. Cell Death Differ 2003. 10: 193-202

Wei, LX, Zhou, J.N., Roberts, A.I., Shi, Y.F. 2003. Lymphocyte Reduction Induced by Hindlimb Unloading: Distinct Mechanisms in the Spleen and Thymus. Cell Res 13:465-71.

Shi, YF, Devadas, S, Greeneltch, KM, Yin, D, Allan Mufson, R and Zhou, J. 2003. Stressed to death: Implication of lymphocyte apoptosis for psychoneuroimmunology. Brain Behav Immun. 17: 18-26.

Zhang, XJ, Yang, L, Zhao, Q, Caen, JP, He, HY, Jin, QH, Guo, LH, Alemany, M, Zhang, LY and Shi, YF. Induction of acetylcholinesterase expression during apoptosis in various cell types. Cell Death Differ 2002. 9: 790-800.

Yin, D, Tuthill, D, Mufson, RA and Shi, YF. 2000. Chronic restraint stress promotes lymphocyte apoptosis by modulating CD95 expression. J Exp Med. 191: 1423-1428.

Yin, D, Mufson, RA, Wang, R and Shi, YF. 1999. Fas-mediated cell death promoted by opioids. Nature, 397: 218.

Shi, YF, Glynn, JM, Guilbert, LJ, Cotter, TG, Bissonnette, RP and Green, DR. 1992. Role for c-myc in activation-induced apoptotic cell death in T cell hybridomas. Science 257: 212-214. (with cover illustration)

Shi, YF, Sahai, BM and Green, DR. 1989. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature, 339: 625-626.

Books Edited

Shi, Y. B., Y. F. Shi, D. W. Scott, and Y. H. Xu. 1997. Current Advances in Programmed Cell Death. Plenum Publishing Corp., New York.

Shi, Y. F., J. Cidlowski, D. W. Scott, and Y. B. Shi. 2003. Molecular Mechanisms of Programmmed Cell Death. Kluwer Academic/Plenum Publishers, New York..

Lab Staff

Joyti Das	Research Teaching Specialist
Satish Devadas	Research Teaching Specialist
Art Roberts	Research Teaching Specialist
Guangwu Xu	Research Teaching Specialist
Zeng-Rong Yuan	Research Teaching Specialist
Liying Zhang	Research Teaching Specialist
Guangwen Ren	Graduate Student
Yingyu Zhang	Graduate Student
Jimin Zhang	Graduate Student
Xiaojuan Xu	Lab Assistant

Research Interests

Mechanisms of Apoptosis in T Helper Subsets

Investigating the molecular mechanisms that controls activation-induced cell death (AICD) in various T cell types has been one of the major focuses of Dr. Shi’s laboratory. Their recent efforts have been on elucidating the differences of the mechanisms that control AICD in Th1 and Th2 cells as well as Tc1 and Tc2 cells. They have shown that while Th1 cells die by the Fas-mediated caspase pathway, Th2 cells die through intracellular release of granzyme B. They also found that prostaglandin E2 (PGE2) specifically protected Th2 cells from AICD by downregulating granzyme B. Thus, differences in the expression of, and susceptibility to, death effectors are a built-in mechanism that controls the Th1-Th2 as well as Tc1-Tc2 balance. One example is severer antigen induced asthma in granzyme B deficient mice.

Identification of the function of MHC class Ib restricted CD8+ T cells.

Unlike T cells restricted by major histocompatibility complex (MHC) class Ia or class II molecules, T cells restricted by MHC class Ib demonstrate properties of both innate and adaptive immunity and are therefore considered innate-like lymphocytes (ILLs). ILLs are believed to have immunoregulatory functions, but their roles in autoimmunity and defense against infections remain elusive. To study the properties of ILLs, Dr. Shi’s group generated mice expressing only MHC class Ib by crossing CIITA(-/-) with K(b-/-)D(b-/-) mice. Surprisingly, these mice developed a lymphoproliferative syndrome and autoimmunity, most notably inflammatory bowel disease (IBD) and insulitis. The CD8(+) ILLs in these mice exhibit a constitutively activated phenotype, and depletion of these cells abolished the autoimmune disorders. In addition, adoptive transfer of CD8(+) ILLs from K(b-/-)D(b-/-)CIITA(-/-) mice to Rag-1(-/-)pfn(-/-) mice also resulted in IBD and insulitis. These findings provide direct evidence that CD8(+) ILLs are sufficient to initiate and mediate autoimmune diseases.

Regulation of RANKL expression in T cells

The ligand for receptor-activator of NF-kB (RANKL) plays a critical role in the homeostasis of bone metabolism, arthritis, immune regulation as well as cancer metastasis. They have shown that the expression of RANKL in T cells is mediated by TCR activation-induced Ca2+ mobilization. One major mechanism that regulates the expression of RANKL was found to be due to the regulation of messenger RNA decay. They have identified that a specific region in the 3’-end of the RANKL mRNA is critical in controlling the decay rate. They are currently investigating how TCR and PGE2 control RANKL mRNA stability in the context of autoimmune arthritis pathogenesis.

Regulation of Immunosuppression by Mesenchymal Stem Cells and Apoptotic Cells

Dr. Shi’s lab has been studying the mechanisms of bone marrow derive mesenchymal stem cells in the regulation of immunosuppression in the last year. They have shown that mesenchymal stem cells have a dramatic effect on lymphocyte activation and proliferation. In vivo administration of mesenchymal stem cells could prevent the rejection of allogeneic skin grafts. Such an immunosuppressive effect was not innate to mesenchymal stem cells, rather induced by cytokines produced by lymphocytes. They are investigating the cellular and molecular mechanisms that mediate such strong immunosuppressive effects by this specialized cell population and hope to develop new strategies for clinical applications.

Dr. Shi’s group has shown that apoptotic cells can prevent heart transplant rejection. They have found that the interaction of apoptotic call educated dendritic cells with normal dendritic cells is crucial in mediating such a tolerigenic effect. They have recently established an in vivo system to investigate cell interactions during this tolerance induction process. In addition, they also studied the role of apoptotic cells in the immune response to tumors and with the goal of determining the effect of apoptotic cells in tolerance induction in the tumor microenvironment.

Stress and the Immune System

Physical and psychological stressors have significant effects on the immune system. Their studies have shown that the reduction in lymphocyte numbers caused by chronic restraint in mice occurs through endogenous opioid-mediated Fas upregulation, which in turn mediates apoptosis. Dr. Shi’s group has recently found similar results with the mouse hindlimb unloading model, an experimental system simulating some of the deleterious effects of spaceflight. Hindlimb suspension was found to drastically deplete various cell populations in the spleen and thymus. Surprisingly, administration of opioid antagonists or interference with the Fas-FasL interaction was able to block the reduction in splenocytes, but not thymocytes. On the other hand, steroid receptor antagonists blocked lymphocyte losses in both spleen and thymus. Therefore, the effects of hindlimb suspension on the homeostasis of splenocytes and thymocytes must be exerted through distinct mechanisms. To elucidate which cells are responsible for the induction of apoptosis during hindlimb suspension, they depleted CD4+CD25+ cells and found that this treatment could protect splenocytes. In addition, mice depleted of CD4+CD25+ cells are protected from the immunosuppression caused by hindlimb suspension.