Shan He

University of Michigan, Ann Arbor, MI, United States

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Publications (11)65.23 Total impact

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    ABSTRACT: Post-transcriptional modification of histones by methylation plays important roles in regulating Ag-driven T-cell responses. We have recently drawn correlations between allogeneic T-cell responses and the histone methyltransferase Ezh2, which catalyzes histone H3 lysine 27 trimethylation. The functional relevance of Ezh2 in T-cell alloimmunity remains unclear. Here, we identify a central role of Ezh2 in regulating allogeneic T cell proliferation, differentiation and function. Conditional loss of Ezh2 in donor T cells inhibited GVHD in mice after allogeneic BM transplantation. Although Ezh2-deficient T cells were initially activated to proliferate upon alloantigenic priming, their ability to undergo continual proliferation and expansion was defective during late stages of GVHD induction. This effect of Ezh2 ablation was largely independent of the proapoptotic molecule Bim. Unexpectedly, as a gene silencer, Ezh2 was required to promote the expression of transcription factors Tbx21 and Stat4. Loss of Ezh2 in T cells specifically impaired their differentiation into IFN-γ-producing effector cells. However, Ezh2 ablation retained anti-leukemia activity in alloreactive T cells, leading to improved overall survival of the recipients. Our findings justify investigation of modulating Ezh2 as a therapeutic strategy for the treatment of GVHD and other T cell-mediated inflammatory disorders.
    Blood 10/2013; · 9.06 Impact Factor
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    ABSTRACT: During immune responses, T cells require tightly controlled expression of transcriptional programs to regulate the balance between beneficial and harmful immunity. These transcriptional programs are critical for the lineage specification of effector T cells, the production of effector cytokines and molecules, and the development and maintenance of memory T cells. An emerging theme is that post-translational modification of histones by methylation plays an important role in orchestrating the expression of transcriptional programs in T cells. In this article, we provide a broad overview of histone methylation signatures for effector molecules and transcription factors in T cells, and the functional importance of histone methyltransferases in regulating T-cell immune responses.
    Immunotherapy 09/2013; 5(9):989-1004. · 2.39 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what APCs is important for priming graft-versus-host reaction remains unknown. We demonstrate that δ-like ligand-4 (Dll4) and Dll4-positive (Dll4(high)) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4(high) i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4(high) i-DCs were CD11c(+)B220(+)PDCA-1(+), resembling plasmacytoid dentritic cells (pDCs) of naive mice. However, as compared with unstimulated pDCs, Dll4(high) i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2, and CD11b, and produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4(low)) i-DCs were CD11c(+)B220(-)PDCA-1(-), and had low levels of Jagged1. In vitro assays showed that Dll4(high) i-DCs induced significantly more IFN-γ- and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4(low) i-DCs. This effect could be blocked by anti-Dll4 Ab. In vivo administration of Dll4 Ab reduced donor-alloreactive effector T cells producing IFN-γ and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4(high) i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4(low) i-DCs. Furthermore, Dll4 and Dll4(high) i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4(high) i-DCs.
    The Journal of Immunology 02/2013; · 5.52 Impact Factor
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    ABSTRACT: Histone methylation is thought to be important for regulating Ag-driven T-cell responses. However, little is known about the effect of modulating histone methylation on inflammatory T-cell responses. We demonstrate that in vivo administration of the histone methylation inhibitor 3-deazaneplanocin A (DZNep) arrests ongoing GVHD in mice after allogeneic BM transplantation. DZNep caused selective apoptosis in alloantigen-activated T cells mediating host tissue injury. This effect was associated with the ability of DZNep to selectively reduce trimethylation of histone H3 lysine 27, deplete the histone methyltransferase Ezh2 specific to trimethylation of histone H3 lysine 27, and activate proapoptotic gene Bim repressed by Ezh2 in antigenic-activated T cells. In contrast, DZNep did not affect the survival of alloantigen-unresponsive T cells in vivo and naive T cells stimulated by IL-2 or IL-7 in vitro. Importantly, inhibition of histone methylation by DZNep treatment in vivo preserved the antileukemia activity of donor T cells and did not impair the recovery of hematopoiesis and lymphocytes, leading to significantly improved survival of recipients after allogeneic BM transplantation. Our findings indicate that modulation of histone methylation may have significant implications in the development of novel approaches to treat ongoing GVHD and other T cell-mediated inflammatory disorders in a broad context.
    Blood 11/2011; 119(5):1274-82. · 9.06 Impact Factor
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    ABSTRACT: The inflammatory T-cell response is important for protecting the host against infections and tumors. However, dysregulated generation of effector T cells produces high levels of inflammatory cytokines and cytotoxic molecules and may cause inflammatory disorders, such as chronic infections, autoimmune diseases and graft-versus-host disease after allogeneic bone marrow transplantation. Thus, tight regulation of effector T cells is essential. Accumulating evidence indicates that Notch plays critical roles in regulating the differentiation of antigen activated T cells into distinct lineages of effector T cells. Furthermore, significant progress has been made in the development of new methods in order to modulate Notch for disease treatment. In this article, we will discuss recent findings that help to gain insight into the impact of Notch in the regulation of effector T cells and highlight the beneficial effects of modulating Notch in inflammatory diseases.
    Immunotherapy 11/2011; 3(11):1353-66. · 2.39 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD), a life-threatening complication after allogeneic hematopoietic stem cell transplantation, is caused by alloreactive donor T cells that trigger host tissue damage. The inflammatory environment inside recipients is critical for GVHD pathogenesis, but the underpinning mechanisms remain elusive. Using mouse model of human GVHD, we demonstrate osteopontin (OPN), a potent proinflammatory cytokine, plays an important role in regulating activation, migration, and survival of alloreactive T cells during GVHD. OPN was significantly elevated after irradiation and persisted throughout the course of GVHD. Blockade of OPN attenuated GVHD with reduced accumulation of donor T cells in recipient organs. Amelioration was the result of migration and survival suppression caused by anti-OPN treatment on donor-derived T cells for 2 reasons. First, OPN promoted the migration and infiltration of naive and alloreactive CD8(+) T cells into host organs. Second, it also facilitated activation and viability of donor-derived CD8(+) T cells via synergizing with T-cell receptor/CD3 signaling. Finally, anti-OPN treatment retained graft-versus-leukemia effect of alloreactive CD8(+) T cells. This study demonstrates, to our knowledge for the first time, the critical effect of OPN in the initiation and persistence of CD8(+) T cell-mediated GVHD and validates OPN as a potential target in GVHD prevention.
    Blood 02/2011; 117(5):1723-33. · 9.06 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4(+) and CD8(+) T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4(+) T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4(+) T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.
    Blood 01/2011; 117(1):299-308. · 9.06 Impact Factor
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    ABSTRACT: Cellular metabolism plays a critical role in regulating T cell responses and the development of memory T cells with long-term protections. However, the metabolic phenotype of antigen-activated T cells that are responsible for the generation of long-lived memory cells has not been characterized. Using lymphocytic choriomeningitis virus (LCMV) peptide gp33-specific CD8(+) T cells derived from T cell receptor transgenic mice, we characterized the metabolic phenotype of proliferating T cells that were activated and expanded in vitro in the presence or absence of rapamycin, and determined the capability of these rapamycin-treated T cells to generate long-lived memory cells in vivo. Antigen-activated CD8(+) T cells treated with rapamycin gave rise to 5-fold more long-lived memory T cells in vivo than untreated control T cells. In contrast to that control T cells only increased glycolysis, rapamycin-treated T cells upregulated both glycolysis and oxidative phosphorylation (OXPHOS). These rapamycin-treated T cells had greater ability than control T cells to survive withdrawal of either glucose or growth factors. Inhibition of OXPHOS by oligomycin significantly reduced the ability of rapamycin-treated T cells to survive growth factor withdrawal. This effect of OXPHOS inhibition was accompanied with mitochondrial hyperpolarization and elevation of reactive oxygen species that are known to be toxic to cells. Our findings indicate that these rapamycin-treated T cells may represent a unique cell model for identifying nutrients and signals critical to regulating metabolism in both effector and memory T cells, and for the development of new methods to improve the efficacy of adoptive T cell cancer therapy.
    PLoS ONE 01/2011; 6(5):e20107. · 3.73 Impact Factor
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    ABSTRACT: We previously found that dendritic cell (DC) precursors could be recruited into the peripheral blood of B6 mice by administration of macrophage inflammatory protein (MIP)-1alpha. These MIP-1alpha-recruited DCs could induce anti-tumor protective immunity when pulsed with tumor cell lysate. In this study, MIP-1alpha-recruited DCs could not effectively suppress preestablished tumor when pulsed with B16 tumor cell lysate. However, inoculation with these DCs expressing MAGE-1 induced an anti-tumor immunity against preestablished solid and metastatic tumor from B16-MAGE-1 cells. These MIP-1alpha-recruited DCs expressed higher level of CCR7 and displayed a more significant chemotactic response toward secondary lymphoid tissue. Therefore, they are superior in the induction of cytotoxic T lymphocytes and the inhibition of tumor development and metastasis than bone marrow-derived DCs. This study established a novel approach to the treatment of preestablished solid and metastatic tumors using MIP-1alpha-recruited DCs transduced with tumor antigen gene.
    Cancer letters 03/2010; 295(1):17-26. · 4.86 Impact Factor
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    ABSTRACT: Chemokines and chemokine receptors play critical roles in directing the migration of alloreactive donor T cells into graft-vs-host disease (GVHD) target organs. However, blockade of GVHD by antagonist Ab against chemokine receptors remains an elusive goal. Using a mouse model of human GVHD, we demonstrate that in vivo administration of anti-CXCR3 Ab for 21 days (long-term), but not for 7 days (short-term), inhibits alloreactive CD8(+) T cell-mediated GVHD. During a graft-vs-host reaction, infused donor CD8(+) T cells generate two subsets of potent inducers of GVHD: CXCR3(+)CD8(+) and CXCR3(-)CD8(+) T cells. Compared with CXCR3(+)CD8(+) T cells, CXCR3(-)CD8(+) T cells produce less granzyme B, Fas ligand, IFN-gamma, and TNF-alpha. Interestingly, stimulation with either dendritic cells or IL-2 induces a dynamic conversion between CXCR3(+)CD8(+) and CXCR3(-)CD8(+) T cells. Short-term anti-CXCR3 Ab treatment inhibits only CXCR3(+)CD8(+) T cell-mediated GVHD, but not the disease induced by CXCR3(-)CD8(+) T cells. Prolonged in vivo administration of anti-CXCR3 Ab significantly reduces the infiltration of alloreactive CD8(+) T cells into GVHD target organs and inhibits GVHD mediated by either CXCR3(+)CD8(+) or CXCR3(-)CD8(+) T cells. Thus, we have established a novel and effective approach with the potential to give rise to new clinical methods for preventing and treating GVHD after allogeneic hematopoietic stem cell transplantation.
    The Journal of Immunology 01/2009; 181(11):7581-92. · 5.52 Impact Factor
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    ABSTRACT: Acquisition of dendritic cells (DCs) or DC precursors in vitro is critical for DC-based immunotherapy. We reported previously that administration of MIP-1alpha mobilized a population of F4/80(-)B220(-)CD11c+ DC precursors into peripheral blood by the expression of CCR1 and CCR5. In this study, we identified a new subset of CCR6+CCR1(-)CCR5(-)B220(-)CD11c(+) cells in MIP-1alpha-administered mice. When cultured with GM-CSF, IL-4, and TNF-alpha, these cells differentiated into mature DCs, possessing the typical morphologic characteristics, phenotypes, and antigen-presenting function (termed CCR6+ DC precursors). Although it did not directly drive the CCR6+ DC precursors, MIP-1alpha could recruit a population of F4/80+CD11c(-) monocyte/macrophage-producing MIP-3alpha in the peripheral blood to mobilize a CCR6+ DC precursor subset of B220(-)CD11c+ DC precursors. Importantly, exogenous administration of MIP-3alpha significantly enhanced MIP-1alpha-induced mobilization of DC precursors. Moreover, these MIP-3alpha- and MIP-1alpha-mobilized DC precursors could be prepared for a DC vaccine capable of eliciting CTL responses to tumor cells, leading to tumor rejection in vitro and in vivo. Taken together, this study further demonstrates the mechanism of DC precursor mobilization induced by MIP-1alpha; that is, besides mobilizing DC precursors with CCR1 and CCR5 expressions, MIP-1alpha recruited F4/80+CD11c(-) monocyte/macrophage-producing MIP-3alpha, which finally mobilized the CCR6+ DC precursor subset to amplify the B220(-)CD11c+ DC precursor population. Furthermore, combined administration of MIP-3alpha and MIP-1alpha may be an efficient strategy for collecting a large number of DCs appropriate for immunotherapy.
    Journal of Leukocyte Biology 10/2008; 84(6):1549-56. · 4.57 Impact Factor

Publication Stats

66 Citations
34 Downloads
731 Views
65.23 Total Impact Points

Institutions

  • 2013
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2009–2011
    • Shanghai Institutes for Biological Sciences
      • Institute of Health Sciences
      Shanghai, Shanghai Shi, China
  • 2010
    • Shanghai Jiao Tong University
      Shanghai, Shanghai Shi, China
  • 2008
    • Northeast Institute of Geography and Agroecology
      • Institute of Health Sciences
      Beijing, Beijing Shi, China