Michael J. Lenardo, M.D.
Chief, Molecular Development of the Immune System Section
Description of Research Program
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 goal is to understand the pathogenesis of autoimmunity from the vantage point of T-cell regulation as well as to develop novel means of diagnosis and immunomodulation of these diseases. Specifically, we are attempting to pioneer a means of antigen-specific induction of apoptosis of pathogenic T cells as a means of treating autoimmune disease. We have also undertaken the investigation of how HIV causes the death of CD4 T lymphocytes. Such studies could lead to a better understanding of viral pathogenesis as well as the development of new treatments for, or vaccines against, AIDS.
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.
Research Group Members
Front row (on the floor) from right: Fengyi Wan, Pushpa Pandiyan, Bernice Lo, Sophia Koessel, Benjamin Chaigne-Delalande
2nd row (sitting on the divan) from right: Maria G. Hessie, Feng-Yen Li, Nicole Yung, Angela Beckon, Carol Trageser, Zhihua Liu, Ping Jiang
3rd row (standing) from right: Mike Lenardo, Monika Jung, Hossam Ashour, Wei Lu, Andy Johnson, Tony Barnitz, Jae Won Lee, Andy Snow, Lixin Zheng
Selected Publications
(View list in PubMed.)
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.
Snow AL, Pandiyan P, Zheng L, Krummey SM, Lenardo MJ. The power and the promise of restimulation-induced cell death in human immune diseases. Immunol Rev. 2010 Jul;236:68-82.
Freundt EC, Yu L, Goldsmith CS, Welsh S, Cheng A, Yount B, Liu W, Frieman MB, Buchholz UJ, Screaton GR, Lippincott-Schwartz J, Zaki SR, Xu XN, Baric RS, Subbarao K, Lenardo MJ. The open reading frame 3a protein of severe acute respiratory syndrome-associated-coronavirus promotes membrane rearrangement and cell death. J Virol. 2010 Jan;84(2):1097-109.
Snow AL, Marsh RA, Krummey SM, Roehrs P, Young LR, Zhang K, van Hoff J, Dhar D, Nichols KE, Filipovich AH, Su HC, Bleesing JJ, Lenardo MJ. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J Clin Invest. 2009 Oct;119(10):2976-89.
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