Michael L. Dustin, Ph.D.
Irene Diamond Associate Professor of Immunology and Associate Professor of Pathology,
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
Dustin ML, Sanders ME, Shaw S, Springer TA.
Dustin ML, Ferguson LM, Chan PY, Springer TA, and Golan DE.
Dustin ML, Golan DE, Zhu DM, Miller JM, Meier W, Davies EA, van der Merwe PA.
Grakoui A, Bromley SK, Sumen C, Davis MM, Shaw AS, Allen PM, Dustin ML.
Carrasco YR, Fleire SJ, Cameron T, Dustin ML, Batista FD.
Yokosuka T, Sakata-Sogawa K, Kobayashi W, Hiroshima M, Hashimoto-Tane A, Tokunaga M, Dustin ML, Saito T.
Campi G, Varma R, Dustin ML.
Varma, R., G. Campi, T. Yokosuka, T. Saito, and M.L. Dustin.
Mossman KD, Campi G, Groves JT, Dustin ML.
Tseng SY, Liu M, Dustin ML.
Bromley SK, Peterson DA, Gunn MD, Dustin ML.
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin, Gan WB.
Kim, J, ML Dustin.
Geissmann F, Cameron TO, Sidobre S, Manlongat N, Kronenberg M, Briskin MJ, Dustin ML, Littman DR.
Lindquist RL, Shakhar G, Dudziak D, Wardemann H, Eisenreich T, Dustin ML, MC Nussenzweig.
Shakhar G, Lindquist RL, Skokos D, Dudziak D, Huang JH, Nussenzweig MC, Dustin ML.
Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ, Dustin ML.