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Faculty Biographies

Michael L. Dustin, Ph.D.

Irene Diamond Associate Professor of Immunology and Associate Professor of Pathology,
Department of Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine,
New York University School of Medicine

Michael L. Dustin

Contact Information
Department of Molecular Pathogenesis
Skirball Institute of Biomolecular Medicine
New York University School of Medicine
540 First Avenue
New York, NY 10016 USA
Phone: +1 212-263-3207
Fax: +1 212-263-5711f
E-mail: dustin@saturn.med.nyu.edu
Web site: saturn.med.nyu.edu/research/mp/dustinlab/

 

Research Theme

The focus of my lab is to understand basic aspects of T-cell activation, particularly the role of the physical interaction of T cells and antigen-presenting cells. Major questions include how activation thresholds are set and how innate immune and environmental signals in tissues alter these thresholds. These questions are relevant to therapeutic strategies to boost the immune response in the context of infectious disease and tumor immunotherapy and to suppress the immune response in the context of autoimmunity.

My lab has taken two major approaches to these questions. In the first we have developed a technology for studying receptor-ligand interactions in a physiological, but highly controllable, system using supported planar bilayers to replace one of the interacting cells. This technology is particularly important in the context of the Nanomedicine Development Center (NDC). A second major area is to understand the manner in which environmental signals are integrated with signals from antigen receptors in secondary lymphoid tissues and other tissue sites based on intravital microscopy.

I initially used supported planar bilayers to assay the activity of purified adhesion molecules. In my start-up lab at Washington University School of Medicine, I refined the technology and, together with Paul Allen, Mark Davis, and Andrey Shaw, applied this to the immunological synapse. We discovered that the immunological synapse forms through convergent movement of antigen receptors that are initially engaged in the outside of the nascent synapse to the center of the mature synapse with a surrounding ring of adhesion molecules.

At NYU School of Medicine we have continued to make major advances using the supported planar bilayers and have also trained a number of international labs in these methods including Facundo Batista at Cancer Research U.K. and Takashi Saito at RIKEN in Japan. A major finding from our group has been that sustained signaling in the immunological synapse is not mediated by the central antigen receptor cluster, as originally hypothesized, but by continued formation of microclusters in the periphery that converge on the center (movie 1). Application of nanofabrication technology to the study of the immunological synapse with Jay Groves at the Lawrence Berkeley National Lab has provided further evidence that the periphery of the immunological synapse is a signaling hot spot. We have also discovered the first specific APC mediated restructuring of the immunological synapse based on the cytoplasmic domain of the costimulatory ligand CD80.

Immune responses are initiated in complex 3D tissue environment and it has long been an interest of ours to understand the interplay of signals in the tissue. We defined dominant chemotactic signals that can reset thresholds for T-cell activation by forcing T cells to abandon otherwise stable interactions with antigen presenting cells. This in vitro result led to the hypothesis that chemotactic signals in the tissues set T-cell sensitivity to antigen.

To make further progress in this area it was necessary to observe T-cell migration and antigen responses in vivo in the living animal via two-photon laser scanning microscopy (movie 2). We have characterized the response of microglial cells, immune cells of the brain, and astrocytes to focal injury, discovered that natural killer T cells patrol liver sinusoids, that dendritic cells form sessile networks in the lymph node, that T cell—dendritic cell interactions that lead to tolerance or immunity are remarkably similar, and that polyclonal regulatory T cells decrease the formation of immunological synapse like interactions between autoreactive T cells and dendritic cells in vivo. These were collaborative studies with Wenbiao Gan, Dan Littman, and Juan Lafaille at NYU or Michel Nussenzweig at Rockefeller.

Our work with the NDC focuses on understanding the role of force and organization in T-cell signaling. We have collaborative studies underway with the labs of Michael Sheetz, Lance Kam, Chris Wiggins, Viola Vogel, Joachim Spatz, and other members of the NDC for Mechanical Biology to address these issues.


Background and Education

Michael Dustin is the Irene Diamond Associate Professor of Immunology at NYU School of Medicine. He obtained his Ph.D. in cell and developmental biology from Harvard University in 1990, working in the lab of Timothy A. Springer, Ph.D. Dr. Dustin acquired postdoctoral training with Stuart Kornfeld, M.D. at Washington University School of Medicine. In 1993 he became an assistant professor in the Department of Pathology and Immunology at Washington University School of Medicine and was promoted to associated professor with tenure in 1999. In 2001, Dr. Dustin moved his lab to NYU School of Medicine and became an Investigator of the Skirball Institute of Biomolecular Medicine.

Honors and Awards

 
1983 Phi Beta Kappa
1984 Shields Warren Award, Boston University
1986 Ryan Fellowship, Harvard University
1997 Englicheff Award, Arthritis Foundation
2000 Presidential Early Career Award in Science and Engineering
2000 Highly Cited Researcher in Immunology, Institute for Scientific Information
2001 Keynote Speaker, FASEB Autoimmunity Conference
2004 Special presentation, Workshop on CD1d and NKT cells, Heron Island Australia
2005 Keynote Speaker, University of Texas Immunology Retreat
2006 Keynote Speaker, "Imaging the Immune Synapse" Paris, France
 

Selected Publications

Dustin ML, Sanders ME, Shaw S, Springer TA.
Purified lymphocyte function-associated antigen 3 binds to CD2 and mediates T lymphocyte adhesion.
J Exp Med. 1987;165:677-692.

Dustin ML, Ferguson LM, Chan PY, Springer TA, and Golan DE.
Visualization of CD2 interaction with LFA-3 and determination of the two-dimensional dissociation constant for adhesion receptors in a contact area.
J Cell Biol. 1996;132:465-474.

Dustin ML, Golan DE, Zhu DM, Miller JM, Meier W, Davies EA, van der Merwe PA.
Low affinity interaction of human or rat T cell adhesion molecule CD2 with its ligand aligns adhering membranes to achieve high physiological affinity.
J Biol Chem. 1997;272:30889-30898.

Dustin ML.
Adhesive bond dynamics in contacts between T lymphocytes and glass supported planar bilayers reconstituted with the immunoglobulin related adhesion molecule CD58.
J Biol Chem. 1997;272:15782-15788.

Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML.
The immunological synapse: a molecular machine controlling T cell activation.
Science. 1999;285:221-227.

Carrasco YR, Fleire SJ, Cameron T, Dustin ML, Batista FD.
LFA-1/ICAM-1 interaction lowers the threshold of B cell activation by facilitating B cell adhesion and synapse formation.
Immunity 2004;20:589-599.

Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A, Tokunaga M, Dustin ML, Saito T.
Newly generated T cell receptor microclusters initiate and sustain T cell activation by recruitment of Zap70 and SLP-76.
Nat Immunol. 2005;6:1253-1262.

Campi G, Varma R, Dustin ML.
Actin and agonist MHC-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling.
J Exp Med. 2005;202:1031-1036.

Varma, R., G. Campi, T. Yokosuka, T. Saito, and M.L. Dustin.
T cell receptor proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster.
Immunity. In press, 2006.

Mossman KD, Campi G, Groves JT, Dustin ML.
Altered TCR signaling from geometrically repatterned immunological synapses.
Science. 2005;310:1191-1193.

Tseng SY, Liu M, Dustin ML.
CD80 Cytoplasmic Domain Controls Localization of CD28, CTLA-4, and Protein Kinase C{theta} in the Immunological Synapse.
J Immunol. 2005;175:7829-7836.

Bromley SK, Peterson DA, Gunn MD, Dustin ML.
Cutting Edge: Hierarchy of chemokine receptor and TCR signals regulating T cell migration and proliferation.
J Immunol. 2000;165:15-19.

Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin, Gan WB.
ATP mediates rapid microglial response to local brain injury in vivo.
Nat Neurosci. 2005;8:752-758.

Kim, J, ML Dustin.
Innate response to focal necrotic injury inside the blood brain barrier.
J. Immunol. In press, 2006.

Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML, Littman DR.
Intravascular immune surveillance by CXCR6+ NKT cells patrolling liver sinusoids.
PLoS Biol. 2005;3:e113.

Lindquist RL, Shakhar G, Dudziak D, Wardemann H, Eisenreich T, Dustin ML, MC Nussenzweig.
Visualizing dendritic cell networks in vivo.
Nat Immunol. 2004;5:1243-1250.

Shakhar G, Lindquist RL, Skokos D, Dudziak D, Huang JH, Nussenzweig MC, Dustin ML.
Stable T cell-dendritic cell interactions precede the development of both tolerance and immunity in vivo.
Nat Immunol 2005;6:707-714.

Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ, Dustin ML.
Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo.
J Exp Med. 2006;203:505-511.

 Immunological synapse

Immature dendritic cells in vivo.