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238Zhengyu (Mark) Ma, M.D., Ph.D. <p>Research Scientist</p> <p>Head, T Cell Immunology Laboratory </p>(302) 298-7194 (302) 651-6881 zma@nemours.org Nemours/Alfred I. duPont Hospital for Children 1600 Rockland Road Wilmington, DE 19803 <ul> <li><strong>M.D.</strong> – Qingdao Medical College, Shandong, China </li><li><strong>M.S.</strong> – Chinese Academy of Medical Sciences, Beijing, China </li><li><strong>Ph.D.</strong> – University of Pennsylvania, Philadelphia, Pennsylvania </li><li><strong>Postdoctoral</strong> – The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania </li></ul><p>The T cell Immunology Lab focuses on antigen recognition by T lymphocytes, which is a critical step of immune responses to pathogens. As a main component of the adaptive immune system, T cells kill virus-infected cells and instruct other immune cells to fight invading pathogens. To accomplish these tasks, T cells must first recognize pathogen-derived antigens using T cell receptors (TCRs) expressed on the cell surface.</p> <p>On the basic side of the research, we investigate how antigen-TCR interaction triggers an activation signal from the TCR. The mechanism of TCR signal initiation, also termed the “TCR triggering puzzle”, is one of the few fundamental questions in immunology today that remains unsolved. Since a T cell can only recognize antigens on the surface of a target cell, antigen-TCR interaction takes place at the T cell-target cell interface. In our lab, we tackle the TCR triggering puzzle by studying the antigen-TCR interaction in the context of the complex biochemical and physical microenvironment at the dynamic cell-cell interface. Taking into consideration  the mechanical forces sustained by the antigen-TCR interaction, we have proposed the “Receptor Deformation Model” of TCR triggering, which explains all three aspects of the TCR triggering puzzle (mechanism, sensitivity, specificity) for the first time. We continue to investigate this important question by employing interdisciplinary approaches such as light and atomic force microscopy, polymers, microfabrication and cellular and molecular biology techniques.</p> <p>On the applied side of the research, we develop T cell-based immunotherapies for diseases, such as cancer and allergy, using our expertise in T cell-antigen recognition. Recently, immunotherapy based on adoptive T cell transfer (ACT) has made great strides in treating cancer. In this approach, a patient’s own T cells are genetically engrafted ex vivo with an artificial TCR to recognize cancer cells, then given back to the patient to destroy the cancer cells. A great challenge for ACT to treat solid tumors is to engineer artificial TCRs that specifically recognize tumor cells but spare normal tissues. To address this, we are working on defining the parameters that determine the specificity of engineered TCRs. We are also developing new ways to screen for receptors that are specific for tumor antigens. In addition, we are developing ACT for allergy, especially severe allergic asthma, by designing artificial TCRs that recognize cells responsible for the disease.</p><ul> <li>Define the parameters that govern the specificity and sensitivity of artificial TCRs. </li><li>Develop a novel approach for generating antigen-specific binders for artificial TCRs. </li><li>Test the design of artificial TCRs for allergic diseases. </li><li>Determine the mechanical strength of antigen-TCR binding. </li></ul><ul> <li><strong>Zhengyu (Mark) Ma, M.D, Ph.D.</strong> - Principal Investigator </li><li><strong>Brittany Fay, B.S.</strong> -  Research Assistant </li><li><strong>Adebomi Adejuwon, B.S.</strong> – Graduate Student </li><li><strong>Karen Christie, B.S.</strong> – Graduate Student </li></ul><ol> <li><strong>Ma Z</strong>, LeBard DN, Loverde SM, Sharp KA, Klein ML, Discher DE, Finkel TH. TCR triggering by pMHC ligands tethered on surfaces via poly(ethylene glycol) depends on polymer length. <em><strong>PLoS ONE.</strong></em> 2014 Nov 10;9(11):e112292. </li><li>Zhang M*, <strong>Ma Z*</strong>, Selliah N, Weiss G, Genin A, Finkel TH, Cron RQ. The impact of Nucleofection® on the activation state of primary human CD4 T cells. <em><strong>J Immunol Methods</strong></em>. 2014 Jun;408:123-31. PMID: 24910400. (*these authors contributed equally) </li><li>Wei F, Zhong S*, <strong>Ma Z*</strong> , Kong H, Medvec A, Ahmed F, Freeman G, Krogsgaard M, and Riley JL. Strength of PD-1 signaling differentially affects T cell effector functions. <em><strong>PNAS</strong></em>  2013 Jul 2;110(27):E2480-9. PMCID:PMC3703988. (*these authors contributed equally) </li><li><strong>Ma Z</strong>, Discher DE and Finkel TH (2012) Mechanical force in T cell receptor signal initiation. <em><strong>Front. Immun.</strong></em> 2012 3:217. </li><li><strong>Ma Z</strong>, Janmey PA, Sharp KA, Finkel TH. Improved method of preparation of supported planar lipid bilayers as artificial membranes for antigen presentation. <em><strong>Microsc Res Tech.</strong></em> 2011 Dec;74(12):1174-85. </li><li><strong>Ma Z</strong>, Finkel TH. TCR triggering by force. <em><strong>Trends in Immunol.</strong></em> 2010 Jan;31(1):1-6. Epub 2009 Oct 15. (Invited manuscript) </li><li><strong>Ma Z</strong>, Sharp KA, Janmey PA, Finkel TH. Surface-anchored monomeric agonist pMHCs alone trigger TCR with high sensitivity. <em><strong>PLoS Biol.</strong></em> 2008 Feb;6(2):e43. (Highlighted by Editors’ Choice in Science 319:1460, 2008. PMC2253636) </li><li><strong>Ma Z</strong>, Janmey PA, Finkel TH. The receptor deformation model of TCR triggering. <em><strong>FASEB J.</strong></em> 2008 Apr;22(4):1002-8. Epub 2007 Nov 5. </li><li>Behrens EM, Sriram U, Shivers DK, <strong>Ma Z</strong>, Finkel TH, Gallucci S. Complement receptor 3 ligation of dendritic cells results in a tolerogenic phenotype and suppresses stimulatory capacity in a Toll-like receptor and type I interferon independent manner. <em><strong>J Immunol</strong></em>, 2007 May 15; 178(10):6268-6279 </li><li>Yin J, <strong>Ma Z</strong>, Shivers DK, Finkel TH. Effective gene suppression by small interference RNA in hard-to-transfect human T cells. <em><strong>J Immunol Methods</strong></em>, 2006 May 30;312(1-2):1-11 </li><li>Kovacs B, Parry RV, <strong>Ma Z</strong>, Fan E, Shivers DK, Freiberg BA, Thomas AK, Rutherford R, Rumbley CA, Riley JL, Finkel TH. Ligation of CD28 by its natural ligand CD86 in the absence of TCR stimulation induces lipid raft polarization in human CD4 T cells. <em><strong>J Immunol.</strong></em> 2005 Dec 15;175(12):7848-7854. </li><li>Tu Z, Ninos JM, <strong>Ma Z</strong>, Wang JW, Lemos MP, Desponts C, Ghansah T, Howson JM, Kerr WG. Embryonic and hematopoietic stem cells express a novel SH2-containing inositol 5'-phosphatase isoform that partners with the Grb2 adapter protein. <em><strong>Blood.</strong></em> 2001 Oct 1;98(7):2028-38. </li></ol>

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