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Dongfang Liu, PhD

Associate Professor of Inflammation and Epigenetics, Institute for Academic Medicine
Associate Member, Research Institute
Houston Methodist
Weill Cornell Medical College


Phone:
713.441.8807


dliu2@houstonmethodist.org
Biography

Dongfang Liu, Ph.D. is an associate member at Center for Inflammation and Epigenetics in Houston Methodist Research Institute. Dr. Liu received his Ph.D. in Immunology in 2005. He did postdoctoral work at the National Institutes of Health (NIH) from 2005 to 2011. Dr. Liu joined Ragon Institute of MGH, MIT and Harvard in 2011 as a senior research scientist, where he worked on HIV-specific CTL dysfunction. He joined Baylor College of Medicine as a tenure-track assistant professor at the Department of Pediatrics and Department of Pathology & Immunology in 2012. He moved to the Houston Methodist Research Institute as a research scientist in 2015.  

Description of Research

Human cytotoxic lymphocytes include natural killer (NK) cells and cytotoxic T lymphocytes (CTL).  We are interested in studying the biology of human cytotoxic lymphocytes using molecular, biochemical, and single molecule imaging strategies. We are applying live cell imaging and biophysical approaches to study the signaling and vesicular traffic at the immunological synapses (IS) and human lymphocytes dysfunction in chronic infectious diseases such as HIV and HIV-related malignancy. The specific project are as follows:

Mechanism controlling the bidirectional vesicular traffic at cytotoxic immunological synapses: Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells kill virus infected cells and tumor cells through polarized release of the content of lytic granules at the cytotoxic immunological synapse. Previous work demonstrated that cytotoxic immunological synapses include a central region of tightly coupled, bidirectional vesicular traffic (Liu, et al., Immunity, 2009). The molecular machinery that confines bidirectional vesicular components to the center of cytotoxic immunological synapses remains unclear. An important regulatory mechanism in cytolytic lymphocytes is inhibition through inhibitory receptors. The ongoing effects in the laboratory are to determine the signaling components in the control of the bidirectional vesicular traffic at immunological synapses, with a focus on signaling by inhibitory receptors.

The role of Crk family proteins in immune response: Cytolytic lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes (CTL), play an important role in the human immune response to infection and malignancy. How these cells mount an effective immune response to infection and malignancy represents one of the key unsolved problems in immunology today. The main work in our group seeks to identify the mechanism(s) by which a small adaptor protein, CT10 regulator of kinase (Crk), and its receptor-driven phosphorylation control NK cells activation and inhibition.  An essential control of NK cytotoxicity is provided by inhibitory receptors expressing on NK cells. A recent study demonstrated that HLA-E (a ligand for inhibitory receptor, CD94-NKG2A) alone induces Crk (chicken tumor virus no.10 regulator of kinase) phosphorylation in NK cells (Liu et al., Immunity, 2012). The exact functions of Crk in regulation of immune response have not been explored. We are interested in the role of Crk in immune response by leveraging a common immunodeficiency, partial DiGeorge syndrome, as well as a novel NK-specific murine knockout system. 

Immunotherapy for HIV and HIV-related malignancies: As patients live longer with HIV-1, non-Hodgkin’s lymphoma (NHL) becomes an increasingly important clinical issue. At present, it is the second most common malignancy in HIV-infected adult patients. Approximately 10% (now over 3.5 million worldwide) of HIV-infected patients develop lymphoma. Unfortunately, therapies that would normally be used to combat NHL – chemotherapy, radiation and monoclonal antibodies – can actually hasten progression of HIV disease by exacerbating underlying immunosuppression. Highly active antiretroviral therapy (HAART), which is clearly invaluable, does not halt growth or proliferation of NHL, nor does it offer a definitive cure for HIV. Patients live longer, only to succumb to a malignancy for which few weapons are available. This gap in our clinical armamentarium calls for the development of innovative therapies. We are interested in developing innovative therapies for HIV-infected patients with lymphoma, which would provide proof-of-concept for similar multipronged immunotherapy in other disease states where tumors accompany viral infection. 

Education & Training

PhD, Tongji Medical College, Huazhong University of Science and Technology
Publications

Crk adaptor proteins regulate nk cell expansion and differentiation during mouse cytomegalovirus infection
Nabekura, T, Chen, Z, Schroeder, C, Park, T, Vivier, E, Lanier, LL & Liu, D 2018, Journal of Immunology, vol 200, no. 10, pp. 3420-3428. DOI: 10.4049/jimmunol.1701639

Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells
Xiong, W, Chen, Y, Kang, X, Chen, Z, Zheng, P, Hsu, YH, Jang, JH, Qin, L, Liu, H, Dotti, G & Liu, D 2018, Molecular Therapy. DOI: 10.1016/j.ymthe.2018.01.020

PD-1 blocks lytic granule polarization with concomitant impairment of integrin outside-in signaling in the natural killer cell immunological synapse
Huang, Y, Chen, Z, Jang, JH, Baig, MS, Bertolet, G, Schroeder, C, Huang, S, Hu, Q, Zhao, Y, Lewis, DE, Qin, L, Zhu, MX & Liu, D 2018, Journal of Allergy and Clinical Immunology. DOI: 10.1016/j.jaci.2018.02.050

Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function
Lee, YH, Martin-Orozco, N, Zheng, P, Li, J, Zhang, P, Tan, H, Park, HJ, Jeong, M, Chang, SH, Kim, BS, Xiong, W, Zang, W, Guo, L, Liu, Y, Dong, ZJ, Overwijk, WW, Hwu, P, Yi, Q, Kwak, L, Yang, Z, Mak, TW, Li, W, Radvanyi, LG, Ni, L, Liu, D & Dong, C 2017, Cell Research, vol 27, no. 8, pp. 1034-1045. DOI: 10.1038/cr.2017.90

Erratum to Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV
Liu, D, Tian, S, Zhang, K, Xiong, W, Lubaki, NM, Chen, Z & Han, W 2017, Protein and Cell, pp. 1. DOI: 10.1007/s13238-017-0427-1

Heterotrimeric complex of p38 MAPK, PKCd, and TIRAP is required for AP1 mediated inflammatory response
Baig, MS, Liu, D, Muthu, K, Roy, A, Saqib, U, Naim, A, Faisal, SM, Srivastava, M & Saluja, R 2017, International Immunopharmacology, vol 48, pp. 211-218. DOI: 10.1016/j.intimp.2017.04.028

Chimeric antigen receptor (CAR)-modified natural killer cell-based immunotherapy and immunological synapse formation in cancer and HIV
Liu, D, Tian, S, Zhang, K, Xiong, W, Lubaki, NM, Chen, Z & Han, W 2017, Protein and Cell, pp. 1-17. DOI: 10.1007/s13238-017-0415-5

The TLR4–NOS1–AP1 signaling axis regulates macrophage polarization
Srivastava, M, Saqib, U, Naim, A, Roy, A, Liu, D, Bhatnagar, D, Ravinder, R & Baig, MS 2016, Inflammation Research, pp. 1-12. DOI: 10.1007/s00011-016-1017-z

Potential therapeutic targets for inflammation in toll-like receptor 4 (TLR4)-mediated signaling pathways
Roy, A, Srivastava, M, Saqib, U, Liu, D, Faisal, SM, Sugathan, S, Bishnoi, S & Baig, MS 2016, International Immunopharmacology, vol 40, pp. 79-89. DOI: 10.1016/j.intimp.2016.08.026

The planar lipid bilayer system serves as a reductionist approach for studying NK cell immunological synapses and their functions
Bertolet, G & Liu, D 2016, . in Methods in Molecular Biology. vol. 1441, Methods in Molecular Biology, vol. 1441, Humana Press, pp. 151-165. DOI: 10.1007/978-1-4939-3684-7_13

Structured Illumination Microscopy Improves Visualization of Lytic Granules in HIV-1 Specific Cytotoxic T-Lymphocyte Immunological Synapses
Liu, D & Chen, H 2015, AIDS Research and Human Retroviruses, vol 31, no. 9, pp. 866-867. DOI: 10.1089/aid.2014.0363

Imaging of cell-cell communication in a vertical orientation reveals high-resolution structure of immunological synapse and novel PD-1 dynamics
Jang, JH, Huang, Y, Zheng, P, Chan Jo, M, Bertolet, G, Zhu, MX, Qin, L & Liu, D 2015, Journal of Immunology, vol 195, no. 3, pp. 1320-1330. DOI: 10.4049/jimmunol.1403143

COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis
Watkin, LB, Jessen, B, Wiszniewski, W, Vece, TJ, Jan, M, Sha, Y, Thamsen, M, Santos-Cortez, RLP, Lee, K, Gambin, T, Forbes, LR, Law, CS, Stray-Pedersen, A, Cheng, MH, Mace, EM, Anderson, MS, Liu, D, Tang, LF, Nicholas, SK, Nahmod, K, Makedonas, G, Canter, DL, Kwok, PY, Hicks, J, Jones, KD, Penney, S, Jhangiani, SN, Rosenblum, MD, Dell, SD, Waterfield, MR, Papa, FR, Muzny, DM, Zaitlen, N, Leal, SM, Gonzaga-Jauregui, C, Boerwinkle, E, Eissa, NT, Gibbs, RA, Lupski, JR, Orange, JS & Shum, AK 2015, Nature Genetics, vol 47, no. 6, pp. 654-660. DOI: 10.1038/ng.3279

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome
Zheng, P, Noroski, LM, Hanson, IC, Chen, Y, Lee, ME, Huang, Y, Zhu, MX, Banerjee, PP, Makedonas, G, Orange, JS, Shearer, WT & Liu, D 2015, Journal of Allergy and Clinical Immunology, vol 135, no. 5, pp. 1293-1302. DOI: 10.1016/j.jaci.2015.01.011

B cell Rab7 mediates induction of activation-induced cytidine deaminase expression and class-switching in T-dependent and T-independent antibody responses
Pone, EJ, Lam, T, Lou, Z, Wang, R, Chen, Y, Liu, D, Edinger, AL, Xu, Z & Casali, P 2015, Journal of Immunology, vol 194, no. 7, pp. 3065-3078. DOI: 10.4049/jimmunol.1401896

Super-resolution imaging of the natural killer cell immunological synapse on a glass-supported planar lipid bilayer
Zheng, P, Bertolet, G, Chen, Y, Huang, S & Liu, D 2015, Journal of Visualized Experiments, no. 96, e52502. DOI: 10.3791/52502

Dysfunctional HIV-specific CD8+ T cell proliferation is associated with increased caspase-8 activity and mediated by necroptosis
Gaiha, GD, McKim, KJ, Woods, M, Pertel, T, Rohrbach, J, Barteneva, N, Chin, CR, Liu, D, Soghoian, DZ, Cesa, K, Wilton, S, Waring, MT, Chicoine, A, Doering, T, Wherry, EJ, Kaufmann, DE, Lichterfeld, M, Brass, AL & Walker, BD 2014, Immunity, vol 41, no. 6, pp. 1001-1012. DOI: 10.1016/j.immuni.2014.12.011

The adaptor protein Crk in immune response
Liu, D 2014, Immunology and Cell Biology, vol 92, no. 1, pp. 80-89. DOI: 10.1038/icb.2013.64

Controlling natural killer cell responses: Integration of signals for activation and inhibition
Long, EO, Sik Kim, H, Liu, D, Peterson, ME & Rajagopalan, S 2013, Annual Review of Immunology, vol 31, pp. 227-258. DOI: 10.1146/annurev-immunol-020711-075005

TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection
Chen, H, Ndhlovu, ZM, Liu, D, Porter, LC, Fang, JW, Darko, S, Brockman, MA, Miura, T, Brumme, ZL, Schneidewind, A, Piechocka-Trocha, A, Cesa, KT, Sela, J, Cung, TD, Toth, I, Pereyra, F, Yu, XG, Douek, DC, Kaufmann, DE, Allen, TM & Walker, BD 2012, Nature Immunology, vol 13, no. 7, pp. 691-700. DOI: 10.1038/ni.2342