Chen Jianzhu
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Publication Defining the expression hierarchy of latent T-cell epitopes in Epstein-Barr virus infection with TCR-like antibodies(2013) Sim A.C.N.; Too C.T.; Oo M.Z.; Lai J.; Eio M.Y.; Song Z.; Srinivasan N.; Tan D.A.L.; Pang S.W.; Gan S.U.; Lee K.O.; Loh T.K.S.; Chen J.; Chan S.H.; Macary P.A.; MEDICINE; SURGERY; MICROBIOLOGY AND IMMUNOLOGY; OTOLARYNGOLOGY; BIOLOGICAL SCIENCESEpstein-Barr virus (EBV) is a gamma herpesvirus that causes a life-long latent infection in human hosts. The latent gene products LMP1, LMP2A and EBNA1 are expressed by EBV-associated tumors and peptide epitopes derived from these can be targeted by CD8 Cytotoxic T-Lymphocyte (CTL) lines. Whilst CTL-based methodologies can be utilized to infer the presence of specific latent epitopes, they do not allow a direct visualization or quantitation of these epitopes. Here, we describe the characterization of three TCR-like monoclonal antibodies (mAbs) targeting the latent epitopes LMP1 125-133, LMP2A 426-434 or EBNA1 562-570 in association with HLA-A0201. These are employed to map the expression hierarchy of endogenously generated EBV epitopes. The dominance of EBNA1 562-570 in association with HLA-A0201 was consistently observed in cell lines and EBV-associated tumor biopsies. These data highlight the discordance between MHC-epitope density and frequencies of associated CTL with implications for cell-based immunotherapies and/or vaccines for EBV-associated disease.Publication Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway(2018) Ye W.; Chew M.; Hou J.; Lai F.; Leopold S.J.; Loo H.L.; Ghose A.; Dutta A.K.; Chen Q.; Ooi E.E.; White N.J.; Dondorp A.M.; Preiser P.; Chen J.; MEDICINE; MICROBIOLOGY AND IMMUNOLOGY; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOLNatural killer (NK) cells provide the first line of defense against malaria parasite infection. However, the molecular mechanisms through which NK cells are activated by parasites are largely unknown, so is the molecular basis underlying the variation in NK cell responses to malaria infection in the human population. Here, we compared transcriptional profiles of responding and non-responding NK cells following exposure to Plasmodium-infected red blood cells (iRBCs) and identified MDA5, a RIG-I-like receptor involved in sensing cytosolic RNAs, to be differentially expressed. Knockout of MDA5 in responding human NK cells by CRISPR/cas9 abolished NK cell activation, IFN-? secretion, lysis of iRBCs. Similarly, inhibition of TBK1/IKK�, an effector molecule downstream of MDA5, also inhibited activation of responding NK cells. Conversely, activation of MDA5 by liposome-packaged poly I:C restored non-responding NK cells to lyse iRBCs. We further show that microvesicles containing large parasite RNAs from iRBCs activated NK cells by fusing with NK cells. These findings suggest that NK cells are activated through the MDA5 pathway by parasite RNAs that are delivered to the cytoplasm of NK cells by microvesicles from iRBCs. The difference in MDA5 expression between responding and non-responding NK cells following exposure to iRBCs likely contributes to the variation in NK cell responses to malaria infection in the human population. ? 2018 Ye et al. http://creativecommons.org/licenses/by/4.0/.Publication Targeting Epstein-Barr virus transformed B lymphoblastoid cells using antibodies with T-cell receptor like specificities(AMER SOC HEMATOLOGY, 2016-09-08) Lai, Junyun; Tan, Wei Jian; Too, Chien Tei; Choo, Joanna Ai Ling; Wong, Lan Hiong; Mustafa, Fatimah Bte; Srinivasan, Nalini; Lim, Angeline Pei Chiew; Zhong, Youjia; Gascoigne, Nicholas RJ; Hanson, Brendon J; Chan, Soh Ha; Chen, Jianzhu; MacAry, Paul A; Assoc Prof Paul A MacAry; MICROBIOLOGY AND IMMUNOLOGY; NATIONAL UNIVERSITY MEDICAL INSTITUTES; LIFE SCIENCES INSTITUTE; BIOLOGICAL SCIENCES; PAEDIATRICSEpstein-Barr virus (EBV) is an oncovirus associated with several human malignancies including posttransplant lymphoproliferative disease in immunosuppressed patients. We show here that anti-EBV T-cell receptor-like monoclonal antibodies (TCR-like mAbs) E1, L1, and L2 bound to their respective HLA-A∗0201-restricted EBV peptides EBNA1562-570, LMP1125-133, and LMP2A426-434 with high affinities and specificities. These mAbs recognized endogenously presented targets on EBV B lymphoblastoid cell lines (BLCLs), but not peripheral blood mononuclear cells, from which they were derived. Furthermore, these mAbs displayed similar binding activities on several BLCLs, despite inherent heterogeneity between different donor samples. A single weekly administration of the naked mAbs reduced splenomegaly, liver tumor spots, and tumor burden in BLCL-engrafted immunodeficient NOD-SCID/Il2rg-/- mice. In particular, mice that were treated with the E1 mAb displayed a delayed weight loss and significantly prolonged survival. In vitro, these TCR-like mAbs induced early apoptosis of BLCLs, thereby enhancing their Fc-dependent phagocytic uptake by macrophages. These data provide evidence for TCR-like mAbs as potential therapeutic modalities to target EBV-associated diseases.