St. Louis, July 9, 1999 — A paper in today’s Science defines a major step in the complex molecular dance that the immune system performs to protect our bodies from viruses and other foreign invaders. The work may one day suggest ways to thwart inappropriate immune responses that cause early onset diabetes and play a role in other diseases.
"The excitement is that we can now visualize key molecular processes that turn on the immune response," says Michael L. Dustin, Ph.D., associate professor of pathology at Washington University School of Medicine in St. Louis.
A cell called an antigen-presenting cell ingests microbes that get inside the body. The cell cuts apart the microbes and displays pieces of their proteins on its surface like beacons. These beacons, called antigens or MHC-peptide complexes, are inspected by the immune system's helper T cells, which decide whether to mount a response to the invader.
Little was known about how T cells decide whether a new antigen is present or not. This decision requires a period of about an hour after the T cell becomes engaged with the antigen-presenting cell. The Science paper shows the changes that must occur to form a molecular structure called an immunological synapse before a T cell can respond.
Dustin was principal investigator of the study. The lead author, Arash Grakoui, Ph.D., performed many of the experiments while he was a graduate student in the laboratory of co-author Paul M. Allen, Ph.D., the Robert L. Kroc Professor of Pathology.
Other researchers had captured snapshots of a helper T cell interacting with an antigen-presenting cell through a shared protein structure. Dustin and collaborators used an imaging method developed in his lab to make a "movie" version of this interaction while looking closer at the structure, which they defined as an immunological synapse. Co-authors who provided expertise included Howard Hughes Medical Institute Investigator Mark M. Davis, Ph.D., professor of microbiology and immunology at Stanford University School of Medicine and discoverer of the T cell antigen receptor. A key part of the method was the ability to reconstitute the function of an antigen-presenting cell using artificial membranes on a glass slide. The membranes, which mimicked the surface of antigen-presenting cells, contained molecules that were color-coded. This allowed the investigators to interpret the movements of molecules on the surface of the adjoining T cell during the early steps in antigen recognition.
What they saw was a specific rearrangement of proteins in the interface between the artificial membrane and the T cells. The membrane molecules consistently formed a shifting bull's-eye pattern during the first hour of interaction. The final bull’s eye pattern, the immunological synapse, formed only when the correct antigen was present. Both the amount and the quality of the antigen were critical in determining whether a T cell could form a synapse. The immunological synapse remained intact for 60 minutes or more. Formation of a stable immunological synapse predicted T cell activation.
The researchers propose that this molecular reorganization produce a biological machine that allows the T cell to decide whether the correct antigen is present. When the T cell first makes contact with the antigen-presenting cell, a complex series of events begins with specific movements of proteins on the cell surface. Different classes of proteins are directed by the T cell to move in different patterns. When the correct antigen is present, these movements result in the formation of the large bull’s eye pattern characteristic of the immunological synapse. When the wrong antigen is present, the molecules never form the right pattern, and the T cell disengages from the antigen-presenting cell and goes off in search of invading organisms elsewhere. Thus, the remarkable feature of the immunological synapse is that its formation is based on biophysical principles and represents the integration of information received by the T cell.
Using their system, the researchers now can dissect the requirements for synapse formation. Many different membrane proteins are likely to have unique roles in this process. In addition, the biophysical rules that guide each protein also can be uncovered. Therefore, this work has the potential to uncover new factors involved in T cell activation, possibly leading to novel drugs for treating autoimmune diseases, organ transplant rejection, AIDS or cancer.
The researchers also included Andrey S. Shaw, M.D., associate professor of pathology, who developed a theoretical framework for immunological synapse formation and the molecular machine concept with Dustin. Graduate students Shannon K. Bromley in Dustin’s lab and Cenk Sumen in Davis' lab also made important contributions to the research.
This research was funded by grants from the Whitaker Foundation, the Arthritis Foundation, the Howard Hughes Medical Institute and the National Institutes of Health.
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, 285 (5425), 221-226, July 9, 1999.
Review of study: Malissen B. Dancing the Immunological Two-Step. Science, 285 (5425), 207-208, July 9, 1999.
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