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IMMUNOLOGY Glowing Mouse Shows How Immune Alarm Rallies Troops Against InvasionDendritic-cell Tubules Go Out of Their Way to Present Antigen to Correct T Cells Using a new mouse model that literally glows with health-protecting molecules, researchers have rewritten part of the textbook on how the immune system knows when to fight invading germs.
A dendritic cell (top) sends a glowing green tubule of MHC class II molecules carrying an immune-alerting message toward a matching T cell. The picture is a link to a video showing eight minutes of interaction between the two cells, with pictures taken every 10 to 15 seconds. (QuickTime movie courtesy of the lab of Hidde Ploegh) Time-lapse video from a pair of HMS labs shows the way captured antigen fragments may progress to the surface of live dendritic cells, which alert other immune cells to pathogens. Inside a dendritic cell, the video shows, class II major histocompatibility complex (MHC) molecules shoot toward the T cell along surprisingly long tubules as they carry their cargo of antigen peptides. These are the first studies using cells from a new genetically engineered mouse whose MHC class II molecules have been tagged with green fluorescent protein. The study is published in the Aug. 29 Nature. "We assume this dialogue between the dendritic cell and the T cell improves the efficiency of the immune response," said Hidde Ploegh, senior author on the paper and the Edward Mallinckrodt Jr. professor of immunopathology at HMS. The action was recorded by a microscope for viewing living cells that was recently developed in the lab of Tomas Kirchhausen, HMS professor of cell biology at the Center for Blood Research. In a related paper in the same issue of Nature, time-lapse video from researchers at Yale University School of Medicine shows the antigen cargo emerging from tubules onto the surface of live mouse dendritic cells. "It's a really interesting story, how dendritic cells sense and instruct the immune response," said Antonio Lanzavecchia, director of the Institute for Research in Biomedicine in Bellinzona, Switzerland, who studies dendritic cell-T cell interaction. Tracing Dendritic CellsIn the body, dendritic and other antigen-presenting cells initially handle all infections in the body. The dendritic cells lurk in the skin, lungs, gut, and other tissues. On sentry duty, they continually snack on things around them, which might include a pathogenic bacterium. When a dendritic cell has gobbled a germ, it stops snacking and races to the nearest lymph node to alert the T cells, which command the more complex immune responses.
Jan Cerny, Ramiro Massol, Marianne Boes, and Hidde Ploegh (l to r) have documented an intimate interaction between the immune system's dendritic cells and T cells. (Photo by Steve Gilbert) The details have been fuzzy, but scientists believed that the dendritic cell arrived in the lymph node with the antigen complex in full view, like a peacock with all its feathers on display. There, many varieties of T cell swarmed around until the right one came along, since each T cell senses a different kind of germ antigen. Or so the story went. Now it appears that dendritic cells may save most of their antigen cargo for the right T cells. "Within minutes of contacting T cells, class II molecules are directed from the compartment inside the cell via extraordinarily long (up to 50-micron) tubules along the microtubule railroad, right to the dendritic cell-T cell interface," said Jonathan Yewdell, an immunologist at the National Institute of Allergy and Infectious Diseases, in a commentary accompanying the two studies. "In the case of a promiscuous dendritic cell interacting with multiple T cells, multiple tubules form simultaneously to deliver class II molecules to each T cell." In cell cultures where an unsuitable T cell was added, the dendritic cell kept its class II cargo to itself. "It's the first time we have seen that dendritic cells are active players in stimulating antigen presentation to antigen-specific T cells," said HMS postdoctoral fellow Marianne Boes, a member of the Ploegh lab and first author of the Harvard paper. If the tubule talk between the dendritic cell and T cell is as important to the immune system as the researchers think it is, then it is likely that some bacteria can disable this mechanism. "We should be on the lookout for bugs that prevent this dialogue from happening," Ploegh said. "It's a recurring theme of host-pathogen interactions: every move by the immune system is counteracted by a clever adaptation of the bug. It's a never-ending game." Designed by Boes, the mouse is believed to be the first whole-animal model of antigen presentation in real time. Tests show the mouse's immune system is normal and apparently unaffected by the green, glowing protein. For these experiments, Boes began with stem cells from the mouse's bone marrow and cultured them in a test tube to become dendritic cells. About the time the mouse cells were ready to study, Ploegh and Boes heard about a new microscope for viewing living cells. Boes teamed up with Jan Cerny and Ramiro Massol, postdoctoral fellows in Kirchhausen's lab, who collaborated on the imaging studies. In early experiments, the tubules showed up as glowing streams of class II MHC molecules. Other experiments found the tubules formed like train cars--linking up on the tracks of the cell's cytoskeleton. In the related paper, time-lapse video from Yale researchers used another new microscopic technique to show that antigen-hauling MHC class II molecules carry their cargo from the acidic bowels of the dendritic cells to the surface. "The entire world of immunology has been T cell-centric for 20 years," said senior author Ira Mellman, Cell Biology Department chair at Yale, "but it's becoming clear that antigen-presenting cells play an equally important role in initiating or suppressing an immune response." The studies are part of a new era in immunology research in which scientists can see live elements of the immune system, Yewdell said. --Carol Cruzan Morton |
