Nov. 17, 2005 The immune system is highly complex. The cast of characters alone required to marshal an immune response to a foreign invader can number in the millions as the body’s soldiers, T cells, are called into action. What triggers this complex response begins when T cells and dendritic cells, another type of immune cell, form a kind of molecular embrace, or immunological synapse, to relay information about intruders.
The communication between these immune cells hasn’t been well understood because scientists had no suitable techniques to manipulate it. Now that problem has been solved. In a new study scientists at New York University School of Medicine and the University of California, Berkeley, report that they have observed the exchange of information between immune cells that is required to spark a body wide response to infection.
“This is the first time that anyone has been able to physically manipulate the immunological synapse and measure the effect on T cell signaling,” says Michael L. Dustin, Ph.D., the Irene Diamond Associate Professor of Immunology and Associate Professor of Pathology at NYU School of Medicine, and one of the lead authors of the study.
The research by Dr. Dustin and Jay T. Groves of University of California, Berkeley, and their colleagues is a fusion of biology and nanotechnology—devices at the molecular scale. The study sheds new light on the workings of T cells, the body’s most specific and potent line of defense against viruses, bacteria, and other pathogens, says Dr. Dustin who is also an investigator in the molecular pathogenesis program at NYU’s Skirball Institute of Biomolecular Medicine.
The study, published in the November 18, 2005, issue of Science, reveals how T cells analyze and react to the signals of infection at the immunological synapse.
Every T cell wears a unique molecule, called a T cell antigen receptor, on its surface that it uses to detect pieces of foreign proteins called antigens. These receptors exist in astonishing, and for all practical purposes, unlimited variety—allowing the body to recognize any pathogen it might encounter.
Just as police need evidence of a crime to begin an investigation, T cells must recognize a specific antigen before they start to fight an infection. Dendritic cells constantly scour the body for antigens and present these to T cells for review in the lymph nodes. It is a demanding job. “Just 10 dendritic cells can show viral antigens to over a million T cells in a day,” says Dr. Dustin.
Once a T cell’s antigen receptor finds an antigen match, the T cell forms an immunological synapse with a dendritic cell through which it queries the dendritic cell for additional information about the antigen and its source in the body. Is the antigen a danger or simply a harmless food protein? The interrogation may last hours, and if the antigen is deemed a threat the T cell starts multiplying, eventually producing thousands of copies of itself. These T cell clones are capable of killing invaders outright and marshaling other cells to destroy them.
In the new study, Gabriele Campi, a graduate student in Dr. Dustin’s laboratory, and Kaspar Mossman, a graduate student of Dr. Groves’s, created a synthetic dendritic cell using purified antigen and adhesion molecules (molecules that the cell can grip) in a thin fluid coating on a glass surface. In prior studies the antigen was free to move over the entire glass surface, but in this study they set up miniscule chrome barriers, allowing them to modify the pattern of T-cell antigen receptor clusters in the immunological synapse.
Previous research has shown that T cell receptors cluster in a bull’s eye-pattern at the interface between the T cell and the synthetic dendritic cell but the significance of this arrangement has been unknown. Thanks to the chrome barriers, Dr. Dustin and his colleagues discovered that the T cell receptor signal is strongest when they are physically held in the outer ring of the bull’s eye rather than the center.
“We locked the receptors in the periphery and saw enhanced signaling over a prolonged period of time. It was quite a surprise,” says Dr. Dustin. Researchers had speculated that the concentrated bull’s eye structure somehow allowed T cells to maintain their state of activation. But the new work shows that it is actually the outer edge of immunological synapse that boosts activation, not the center.
Dr. Dustin’s group is now conducting additional experiments to see if dendritic cells actively present proteins to T cells in patterns that stimulate the periphery of the bull’s eye in the immunological synapse, using molecular organization to provide information about the precise nature of the threat associated with the antigen.
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