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Laboratory of Immunology

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Michael J. Lenardo, M.D.

Photo of Michael J. Lenardo, M.D.

Chief, Molecular Development of the Immune System Section, LI

Major Areas of Research

  • Genetic diseases of immune homeostasis and autoimmunity
  • Non-apoptotic mechanisms of cell death
  • Development of novel immunodiagnostics and immunotherapeutics
  • Physiology of Mg2+ as a second messenger in signal transduction
 

Program Description

Our laboratory investigates the molecular regulation of T lymphocytes, particularly as it relates to immunological tolerance, apoptosis, and autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus, and similar diseases. We use both molecular biology and cellular immunology techniques to pursue these investigations, with a focus on programs of cell death and survival, including apoptosis, autophagy, and necrosis mechanisms. Our approach has been to use contemporary genomic approaches to discover the molecular basis of new genetic diseases of the immune system that affect activation, tolerance, and homeostasis and to develop novel means of diagnosis and immunomodulation of these diseases. Also, we are attempting to pioneer a means of antigen-specific induction of apoptosis of pathogenic T cells as a means of treating autoimmune disease. Such studies could lead to a better understanding of molecular regulatory mechanisms that are important for human immunological diseases.

 
A model of mature T-cell homeostasis during immune responses
A model of mature T-cell homeostasis during immune responses
Antigen stimulation activates naïve T lymphocytes to produce cytokines that promote T-cell growth, such as IL-2 and IL-4 (other immunoreactive cells express IL-7 in support). These cytokines drive activated T cells to proliferate. After antigenic stimulation, the activated T cells are subject to population control at multiple levels. First, the presence of regulatory T cells (Treg) can deprive the activated T cells of sufficient growth cytokines and trigger cytokine deprivation-induced apoptosis. Secondly, repeated T-cell receptor (TCR)-stimulation by an antigen can cause TCR re-stimulation-induced cell death (RICD). Lastly, at the end phase of an immune response, lacking IL-2 and other survival cytokines leads activated T cells to undergo cytokine withdrawal-induced apoptosis (CWID). A small fraction of activated T cells may develop into memory T cells provided with appropriate microenvironments. By all means, T cell-dependent immunity and homeostasis are maintained by balancing between proliferation and contraction of antigen-specific T-cell populations.
 

Biography

Dr. Lenardo graduated with a B.A. from the Johns Hopkins University and an M.D. from Washington University, St. Louis. He performed clinical work in internal medicine and research at the University of Iowa and received postdoctoral training at the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology. He established an independent research unit in the Laboratory of Immunology in 1989 and became a senior investigator and section chief in 1994. Dr. Lenardo serves on several editorial boards and has given numerous lectures around the world on his work on the molecular regulation of immune homeostasis. His work focuses on lymphocyte apoptosis, autoimmunity, and genomics of the immune system. He was one of the founders of the NIH-Oxford-Cambridge Scholars program for doctoral training and the NIH M.D./Ph.D. partnership program.

Research Group

Front row from right: Sonia Majri, Chryssa Kanellopoulou, Bernice Lo, Michael Lenardo, Carol Trageser, Maria Hessie, Ping Jiang, Pearl Chen

2nd row from right: Nicole Yung, Helen Matthews, Carrie Lucas, Jian Li, ByungHa Lee, Rebecca Baker, Austin Swafford, Martha Dalton, Wei Lu

3rd row from right: Lixin Zheng, Matt Biancalana, Benjamin Chaigne-Delalande, Daniel Brooks, Kim Shafer-Weaver, Tim Gilpatrick

 
Lenardo Group, August 2013
 

Selected Publications

Chaigne-Delalande B, Li FY, O'Connor GM, Lukacs MJ, Jiang P, Zheng L, Shatzer A, Biancalana M, Pittaluga S, Matthews HF, Jancel TJ, Bleesing JJ, Marsh RA, Kuijpers TW, Nichols KE, Lucas CL, Nagpal S, Mehmet H, Su HC, Cohen JI, Uzel G, Lenardo MJ. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science. 2013 Jul 12;341(6142):186-91.

Snow AL, Xiao W, Stinson JR, Lu W, Chaigne-Delalande B, Zheng L, Pittaluga S, Matthews HF, Schmitz R, Jhavar S, Kuchen S, Kardava L, Wang W, Lamborn IT, Jing H, Raffeld M, Moir S, Fleisher TA, Staudt LM, Su HC, Lenardo MJ. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J Exp Med. 2012 Nov 19;209(12):2247-61.

Liu Z, Lee J, Krummey S, Lu W, Cai H, Lenardo MJ. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol. 2011 Oct 9;12(11):1063-70.

Li FY, Chaigne-Delalande B, Kanellopoulou C, Davis JC, Matthews HF, Douek DC, Cohen JI, Uzel G, Su HC, Lenardo MJ. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature. 2011 Jul 27;475(7357):471-6.

Pandiyan P, Conti HR, Zheng L, Peterson AC, Mathern DR, Hernández-Santos N, Edgerton M, Gaffen SL, Lenardo MJ. CD4(+)CD25(+)Foxp3(+) regulatory T cells promote Th17 cells in vitro and enhance host resistance in mouse Candida albicans Th17 cell infection model. Immunity. 2011 Mar 25;34(3):422-34.

Yu L, McPhee CK, Zheng L, Mardones GA, Rong Y, Peng J, Mi N, Zhao Y, Liu Z, Wan F, Hailey DW, Oorschot V, Klumperman J, Baehrecke EH, Lenardo MJ. Termination of autophagy and reformation of lysosomes regulated by mTOR. Nature. 2010 Jun 17;465(7300):942-6.

Visit PubMed for a complete publication listing.

Patents

Baehrecke EH, Alva A, Lenardo MJ, Li Y, inventors; University of Maryland College Park, National Institutes of Health, assignees. Function of autophagy genes in cell death. United States patent US 7,838,645. 2010 Nov 23.

Lenardo MJ, Chan FKM, Siegel RM, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Identification of a novel domain in the tumor necrosis factor receptor family that mediates pre-ligand receptor assembly and function. United States patent US 7,148,061. 2006 Dec 12.

Nye SH, Lenardo MJ, McFarland HF, Matis LA, Mueller EE, Mueller JP, Pelfrey CM, Squinto SP, Wilkins JA. Modified myelin basic protein molecules. United States patent US 7,041,503. 2006 May 9.

Baltimore D, Sen R, Sharp PA, Singh H, Staudt L, Lebowitz JH, Baldwin AS Jr, Clerc RG, Corcoran LM, Baeuerle PA, Lenardo MJ, Fan CM, Maniatis TP, inventors; President & Fellows of Harvard College, Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research, assignees. Nuclear factors associated with transcriptional regulation. United States patent US 6,410,516. 2002 Jun 25.

Lenardo MJ, Fisher G, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Applicator system. United States patent US 6,312,648. 2001 Nov 6.

Baltimore D, Sen R, Sharp PA, Singh H, Staudt L, Lebowitz JH, Baldwin AS Jr, Clerc RG, Corcoran LM, Baeuerle PA, Lenardo MJ, Fan CM, Maniatis TP, inventors; President & Fellows of Harvard College, Massachusetts Institute of Technology, Whitehead Institute for Biomedical Research, assignees. Nuclear factors associated with transcriptional regulation. United States patent US 6,150,090. 2000 Nov 21.

Visit the U.S. Patent and Trademark Office database for a complete patent listing.

Last Updated January 08, 2014