Yi Zhang, M.D., Ph.D.
Assistant Professor of Internal Medicine
yizha@umich.edu

Research Interests

Hematopoietic stem cell transplantation, GVHD/GVL, Memory T cells,
Stem cell/T cell signaling

Current Research Activity

Our research has focused on epigenetic regulation of T cell-mediated immune responses. Although T cell immunity is clearly important for protecting the host from infections and tumors, inflammatory T cell responses can be detrimental to the host, including autoimmunity, allo-immunity and chronic infections. T cells use epigenetic mechanisms to organize the generation of specialized effector cells during inflammation. The epigenetic effects organize the ability of signal transduction pathways to regulate effector cytokines (e.g., IFN-gamma, IL-4 and IL-17) and their transcriptional factors (e.g., T-bet, GATA3 and RORrt). In addition, epigenetic modifications orchestrate the expression of genes that are essential for the survival, proliferation and fate determination of activated T cells, including genes associated with cell apoptosis and death, cell cycle regulation, DNA replication and repair, stress resistance, transcription regulation and chromatin modification. Thus, targeting epigenetic regulators may identify new strategies to control T cell-mediated inflammation. Specifically, we have developed both genetic and pharmacologic approaches to investigate the impact of histone methyltransferase Ezh2 in antigen-driven T cell responses. Our ultimate goal is to develop novel approaches to treat inflammatory disorders, such as graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (Allo-BMT), graft rejection after organ transplantation and autoimmune diseases.

Allo-BMT is an effective therapy for hematologic diseases and is finding new applications to non-hematologic diseases, such as autoimmune diseases and solid organ transplantation. However, GVHD, a life-threatening complication after allo-BMT, remains the major barrier to the success of the procedure. GVHD is caused by infused donor T cells that recognize and react to histocompatibility differences between the donor and the host. Upon antigen-presenting cell (APC) activation, infused donor T cells become alloreactive effector T cells that produce high levels of inflammatory cytokines and cytotoxic molecules, leading to host tissue injury. Current methods that prevent and treat GVHD lack efficacy and impair the graft-versus-leukemia (GVL) activity of donor T cells. New approaches are urgently required for controlling GVHD while retaining anti-tumor activity. Both genetic and pharmacologic approaches are available to investigate: (1) how Notch signaling regulates allogeneic T cell responses and their-mediated GVHD, and (2) how APCs regulate effector T cell differentiation of allaoantigen-selected T cells through their expression of different Notch ligands. We anticipate gain extraordinary insights into the Notch regulation of inflammatory T cell responses after allo-BMT.

Representative Publications

Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG: Rapid priming in vivo by pre-terminal host dendritic cells triggers donor CD8 T cell-mediated acute graft-versus-host disease in a mouse model. Journal Clinical Investigation 109:1335, 2002.

Zhang Y, Shlomchik W, Joe G, Louboutin JP, Zhu J, Rivera AJ, and Emerson SG: APCs in the liver and spleen recruit activated allogeneic CD8(+) T cells to elicit hepatic graft-versus-host disease. J Immunol 169(12):7111-8, 2002.

Zhang Y, Joe G, Zhu J, Carroll, R, Levine B, Hexner E, June C and Emerson SG. Dendritic Cell Activated CD44 hi CD8 + T Cells Are Defective in Mediating Acute Graft-versus-host Disease but Retain Graft-versus-leukemia Activity. Blood 103(10): 3970-3978, 2004.

Zhang Y, Joe G, Hexner E, Zhu J and Emerson SG. Allogeneic memory T cells are responsible for the persistence of graft-versus-host disease. Journal of Immunology 174(5):3051-8. 2005.

Zhu J, Zhang Y , Joe GJ, Pompetti R, Emerson SG. NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci U S A.102(33):11728-33; 2005.

Zhang Y, Gerard Joe, Elizabeth Hexner, Jiang Zhu, and Stephen G. Emerson, Host-reactive CD8 + Memory Stem Cells in Graft-versus-host Disease. Nature Medicine 2005, 11:1299.

Zhang Y, Elizabeth Hexner, Dale Frank, and Stephen G. Emerson , CD4 + T Cells Generated de novo from Donor Hematopoietic Stem Cells Mediate the Evolution from Acute to Chronic Graft-versus-host Disease. J Immunol . 2007 Sep 1;179(5):3305-14.

He S, Cao Q, Qiu YH, Mi JQ, Zhang JZ, Jin M, Ge HL, Emerson SG, Zhang Y (correspondence author), Zhang YY.  A new approach of blocking alloreactive T cell-mediated GVHD by in vivo Administration of Anti-CXCR3 Neutralizing Antibody. J Immunol 2008 181:7581-7592.

Huang J, Zhang Y, Bersenev A, O’Brien WT, Tong W, Emerson SG, Klein PS. Pivotal role for glycogen synthase kinase-3 in hematopoietic stem cell homeostasis in mice. J. Clin. Invest 2009, 119(12): 3519-3529.

Kato K, Cui S, Kuick R, Mineishi S, Hexner E, Ferrara JLM, Emerson SG, Zhang Y. Identification of stem cell transcriptional programs normally experessed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease.  Biology of Bone Marrow Transplantation. 2010; 16(6):751-71.

Zhang Y, Sandy AR, Wang J, Shan GT, Radojcic V, Tran I, Friedman A, Kato K, He S, Cui S, Hexner E, Frank D, Emerson SG, Pear WS, Maillard I. Notch signaling is a critical regulator of allogeneic CD4+ T cell responses mediating graft-versus-host disease. Blood, 2011, 117:299.

He S, Kato K, Jiang J, Wahl DR, Mineishi S  , Fisher EM, Murasko DM, Glick GD and Zhang Y, Characterization of the metabolic phenotype of rapamycin-resistant CD8+ T cells with augmented ability to generate long-lasting memory cells. PLoS ONE, In printing, 2011.