Zheng Xiang

The University of Hong Kong, Hong Kong, Hong Kong

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Publications (9)75.11 Total impact

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    ABSTRACT: Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human Vγ9Vδ2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through γ/δ-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2(-/-)γc(-/-) mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded Vγ9Vδ2-T cells alone effectively prevented EBV-LPD in Rag2(-/-)γc(-/-) mice and induced EBV-LPD regression in EBV(+) tumor-bearing Rag2(-/-)γc(-/-) mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of Vγ9Vδ2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through Vγ9Vδ2-T cell targeting.
    Cancer Cell 09/2014; · 24.76 Impact Factor
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    ABSTRACT: Although diverse functions of different toll-like receptors (TLR) on human natural regulatory T cells have been demonstrated recently, the role of TLR-related signals on human induced regulatory T cells remain elusive. Previously our group developed an ex vivo high-efficient system in generating human alloantigen-specific CD4(hi)CD25(+) regulatory T cells from naïve CD4(+)CD25(-) T cells using allogeneic CD40-activated B cells as stimulators. In this study, we investigated the role of TLR5-related signals on the generation and function of these novel CD4(hi)CD25(+) regulatory T cells. It was found that induced CD4(hi)CD25(+) regulatory T cells expressed an up-regulated level of TLR5 compared to their precursors. The blockade of TLR5 using anti-TLR5 antibodies during the co-culture decreased CD4(hi)CD25(+) regulatory T cells proliferation by induction of S phase arrest. The S phase arrest was associated with reduced ERK1/2 phosphorylation. However, TLR5 blockade did not decrease the CTLA-4, GITR and FOXP3 expressions, and the suppressive function of CD4(hi)CD25(+) regulatory T cells. In conclusion, we discovered a novel function of TLR5-related signaling in enhancing the proliferation of CD4(hi)CD25(+) regulatory T cells by promoting S phase progress but not involved in the suppressive function of human CD40-activated B cell-induced CD4(hi)CD25(+) regulatory T cells, suggesting a novel role of TLR5-related signals in the generation of induced regulatory T cells.
    PLoS ONE 07/2013; 8(7):e67969. · 3.53 Impact Factor
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    ABSTRACT: γδ-T cells play an indispensable role in host defense against different viruses, including influenza A virus. However, whether these cells have cytotoxic activity against influenza virus-infected lung alveolar epithelial cells and subsequently contribute to virus clearance remains unknown. Using influenza virus-infected A549 cells, human lung alveolar epithelial cells, we investigated the cytotoxic activity of aminobisphosphonate pamidronate (PAM)-expanded human Vγ9Vδ2-T cells and their underlying mechanisms. We found that PAM could selectively activate and expand human Vγ9Vδ2-T cells. PAM-expanded human Vγ9Vδ2-T cells efficiently killed influenza virus-infected lung alveolar epithelial cells and inhibited virus replication. The cytotoxic activity of PAM-expanded Vγ9Vδ2-T cells was dependent on cell-to-cell contact and required NKG2D activation. Perforin-granzyme B, tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas-Fas ligand (FasL) pathways were involved in their cytotoxicity. Our study suggests that targeting γδ-T cells by PAM can potentially offer an alternative option for the treatment of influenza virus.Cellular & Molecular Immunology advance online publication, 28 January 2013; doi:10.1038/cmi.2012.70.
    Cellular & molecular immunology 01/2013; · 3.42 Impact Factor
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    ABSTRACT: Graft-versus-host disease (GVHD) is a lethal complication of allogeneic bone marrow transplantation (BMT). Immunosuppressive agents are currently used to control GVHD but may cause general immune suppression and limit the effectiveness of BMT. Adoptive transfer of regulatory T cells (T(regs)) can prevent GVHD in rodents, suggesting a therapeutic potential of T(regs) for GVHD in humans. However, the clinical application of T(reg)-based therapy is hampered by the low frequency of human T(regs) and the lack of a reliable model to test their therapeutic effects in vivo. Recently, we successfully generated human alloantigen-specific CD8(hi) T(regs) in a large scale from antigenically naïve precursors ex vivo using allogeneic CD40-activated B cells as stimulators. We report a human allogeneic GVHD model established in humanized mice to mimic GVHD after BMT in humans. We demonstrate that ex vivo-induced CD8(hi) T(regs) controlled GVHD in an allospecific manner by reducing alloreactive T cell proliferation as well as decreasing inflammatory cytokine and chemokine secretion within target organs through a CTLA-4-dependent mechanism in humanized mice. These CD8(hi) T(regs) induced long-term tolerance effectively without compromising general immunity and graft-versus-tumor activity. Our results support testing of human CD8(hi) T(regs) in GVHD in clinical trials.
    Science translational medicine 01/2013; 5(168):168ra9. · 10.76 Impact Factor
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    ABSTRACT: Inducible co-stimulator (ICOS) is a member of CD28/Cytotoxic T-lymphocyte Antigen-4 (CTLA-4) family and broadly expressed in activated CD4(+) T cells and induced regulatory CD4(+) T cells (CD4(+) iTreg). ICOS-related signal pathway could be activated by the interaction between ICOS and its ligand (ICOSL). In our previous work, we established a cost-effective system to generate a novel human allo-antigen specific CD4(hi) Treg by co-culturing their naïve precursors with allogeneic CD40-activated B cells in vitro. Here we investigate the role of ICOS in the generation and function of CD4(hi) Treg by interrupting ICOS-ICOSL interaction with ICOS-Ig. It is found that blockade of ICOS-ICOSL interaction impairs the induction and expansion of CD4(hi) Treg induced by allogeneic CD40-activated B cells. More importantly, CD4(hi) Treg induced with the addition of ICOS-Ig exhibits decreased suppressive capacity on alloantigen-specific responses. Dysfunction of CD4(hi) Treg induced with ICOS-Ig is accompanied with its decreased exocytosis and surface CTLA-4 expression. Through inhibiting endocytosis with E64 and pepstatin A, surface CTLA-4 expression and suppressive functions of induced CD4(hi) Treg could be partly reversed. Conclusively, our results demonstrate the beneficial role of ICOS-ICOSL signal pathway in the generation and function of CD4(hi) Treg and uncover a novel relationship between ICOS and CTLA-4.
    PLoS ONE 01/2013; 8(12):e82203. · 3.53 Impact Factor
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    ABSTRACT: Like αβ T cells, human γδ T cells also have different subsets with distinct characteristics. Whether human Vγ9Vδ2 T cells have functionally different subsets in response to influenza A (fluA) viruses remains unknown. In this study, we show for the first time that both central (CD45RA(-)CD27(+)) and effector (CD45RA(-)CD27(-)) memory Vγ9Vδ2 T cells have similar levels of immediate interferon (IFN) γ and cytotoxic responses to human and avian fluA virus-infected cells. In contrast, CD56(+) Vγ9Vδ2 T cells have significantly higher cytotoxicity against fluA virus-infected cells compared with their CD56(-) counterparts, whereas both subsets have similar IFN-γ responses. We further demonstrate that the CD16-dependent degranulation pathway, but not antibody-dependent cell-mediated cytotoxicity, contribute to the superior cytotoxicity of CD56(+) Vγ9Vδ2 T cells. Our study provides further evidence for the phenotypic and functional characterization of human Vγ9Vδ2 T-cell subsets during fluA virus infection and may help improve the γδ T-cell-based immunotherapy for viral infection.
    The Journal of Infectious Diseases 03/2012; 205(11):1646-53. · 5.85 Impact Factor
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    ABSTRACT: γδ T cells are essential constituents of antimicrobial and antitumor defenses. We have recently reported that phosphoantigen isopentenyl pyrophosphate (IPP)-expanded human Vγ9Vδ2 T cells participated in anti-influenza virus immunity by efficiently killing both human and avian influenza virus-infected monocyte-derived macrophages (MDMs) in vitro. However, little is known about the noncytolytic responses and trafficking program of γδ T cells to influenza virus. In this study, we found that Vγ9Vδ2 T cells expressed both type 1 cytokines and chemokine receptors during influenza virus infection, and IPP-expanded cells had a higher capacity to produce gamma interferon (IFN-γ). Besides their potent cytolytic activity against pandemic H1N1 virus-infected cells, IPP-activated γδ T cells also had noncytolytic inhibitory effects on seasonal and pandemic H1N1 viruses via IFN-γ but had no such effects on avian H5N1 or H9N2 virus. Avian H5N1 and H9N2 viruses induced significantly higher CCL3, CCL4, and CCL5 production in Vγ9Vδ2 T cells than human seasonal H1N1 virus. CCR5 mediated the migration of Vγ9Vδ2 T cells toward influenza virus-infected cells. Our findings suggest a novel therapeutic strategy of using phosphoantigens to boost the antiviral activities of human Vγ9Vδ2 T cells against influenza virus infection.
    Journal of Virology 07/2011; 85(19):10109-16. · 5.08 Impact Factor
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    ABSTRACT: There are few antiviral drugs for treating influenza, and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Here, we show that human Vγ9Vδ2 T cells expanded by the aminobisphosphonate pamidronate (PAM) kill influenza virus-infected cells and inhibit viral replication in vitro. In Rag2(-/-)γc(-/-) immunodeficient mice reconstituted with human peripheral mononuclear cells (huPBMCs), PAM reduces disease severity and mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication. PAM has no such effects in influenza virus-infected Rag2(-/-)γc(-/-) mice reconstituted with Vγ9Vδ2 T cell-depleted huPBMCs. Our study provides proof-of-concept of a novel therapeutic strategy for treating influenza by targeting the host rather than the virus, thereby reducing the opportunity for the emergence of drug-resistant viruses. As PAM has been commonly used to treat osteoporosis and Paget's disease, this new application of an old drug potentially offers a safe and readily available option for treating influenza.
    Journal of Experimental Medicine 06/2011; 208(7):1511-22. · 13.21 Impact Factor
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    ABSTRACT: Murine Foxp3(+) Treg have recently been shown to express T-bet, a transcription factor characteristic of Th1 effector cells. A human Treg phenotype equivalent has not been reported. Here, we show that naïve human CD4(+) T cells incubated with low numbers of CD40-activated allogeneic B cells preferentially differentiate into alloantigen-specific CD4(hi) CD25(hi) Treg. These differentiated cells potently suppress effector T-cell responses and express T-bet, IFN-γ, and CXCR3, the features of Th1 effector cells. In contrast, co-culture of naïve CD4(+) T cells with high numbers of allogeneic B cells results in CD4(+) CD25(+) T cells that promote, rather than inhibit, effector T-cell responses, demonstrating the plasticity of CD4(+) T-cell differentiation in response to alloantigen-presenting B cells. The optimal accumulation of CD4(hi) CD25(hi) Treg induced using higher T cell:B cell co-culture ratios was dependent on the expression of T-bet and endogenously produced IFN-γ. Induction of Treg-mediated suppression function in the Treg population was not. As CXCR3 confers the preferential trafficking of T cells to tissue sites of IFN-γ, these human Th1-like Treg might be useful for modulating pathological Th1 effector responses, such as that occurring during graft-versus-host disease or graft rejection.
    European Journal of Immunology 01/2011; 41(1):128-39. · 4.97 Impact Factor

Publication Stats

77 Citations
75.11 Total Impact Points


  • 2011–2014
    • The University of Hong Kong
      • Department of Paediatrics and Adolescent Medicine
      Hong Kong, Hong Kong
  • 2013
    • Sichuan University
      • Department of Pediatrics
      Hua-yang, Sichuan, China