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IMMUNOLOGY
Innate Signal Sparks Homing of T CellsWhen one fast-acting lipid hits the panic button about a wound, invading pathogen, or asthma-triggering antigen, it not only calls in the short-acting attack cells of the innate immune system for immediate battle, it also recruits the first T cells, the better-armed troops of the adaptive immune system that can escalate and sustain the conflict.
Andrew Luster (far right), and postdoctoral fellows (from left) Benjamin Medoff, Andrew Tager, and Shannon Bromley, and their colleagues, showed that a fast-acting lipid, likely from activated mast cells, directs the first specific T cells to trouble spots in the body, where they exacerbate the allergic reaction. (Photo by Graham Ramsay) The results of three studies published together in the October Nature Immunology help explain the uncanny ability of T cells to home to problem areas in the body and suggest potential new mechanisms to treat inflammatory diseases like asthma.
The Lipid AlarmScientists have recently focused on chemokines and adhesion molecules as the main directors of T cell trafficking. But the lipid leukotriene B4 (LTB4) has a hotline to effector T cells, according to the latest studies that show this lipid is required for the early recruitment of both the CD4+ and CD8+ varieties. Effector T cells are those that have already encountered trouble and patrol the blood vessels better armed for a faster, bigger response the next time."LTB4 is a chemoattractant thought to recruit elements of the innate immune system, and now we find the same substance recruits elements of the adaptive immune system," said Stephen Schoenberger, a cellular immunologist at the La Jolla Institute for Allergy and Immunology in San Diego, who wrote a commentary accompanying the papers. "One of the big problems in human health is chronic inflammation," he said. "If we can block the initial effector T cells, maybe we can help to nip the response in the bud." Effector T cells have an uncanny ability to home to sites of infection or inflammation to mediate an effective immune response. Most of the T cells arrive a little later, lured by the irresistible but slower acting scent of chemokines, which require gene expression that can take hours. On the other hand, the lipid LTB4 is synthesized within minutes from the membranes of mast cells (sentinels of the early warning system lining the skin, gut, and airways), macrophages, and other leukocytes. Amplifying an SOSFor Luster, the story began 10 years ago during his postdoctoral fellowship in the HMS lab of Philip Leder, chair of the Department of Genetics. There he cloned an orphan chemoattractant receptor found in high numbers on white blood cells, including some T cell lymphomas. After starting his own lab at MGH, he identified the receptor as BLT1, one of two for LTB4. Soon, postdoctoral fellow Andrew Tager created BLT1 knockout mice and showed that the receptor was the megaphone used by the lipid LTB4 to rally neutrophils and other leukocytes to the scene. In another project, Luster noticed that some early T cells homed to the lung independently of the peptide chemokines that recruit most of the airway-constricting T helper 2 cells.The two lines of work came together in the latest study led by co-first authors Tager, now an HMS instructor in medicine at MGH, and postdoctoral fellow Shannon Bromley. Early in the asthma response, fewer antigen-specific T helper 2 cells (one of two kinds of CD4+ effector cells) reached the airways of BLT1 knockout mice, which also lagged in responsive neutrophils and eosinophils, compared to wild type mice. Other experiments implicated mast cells as the source of lipid LTB4. In asthma, Luster, Tager, and Bromley propose that the lipid pulls antigen-specific CD4+ cells from nearby blood vessels into the airways, where they exacerbate inflammation and make it hard to breathe. The InformantMeanwhile, postdoctoral fellow Katayoon Goodarzi in von Andrian's lab had collaborated with Tager and Luster on the original BLT1 knockout-mouse paper by performing an intravital microscopy analysis. In the latest paper, Goodarzi, now a fellow in transfusion medicine at Beth Israel Deaconess Medical Center, and her colleagues followed up on the same hints from the scientific literature that the lipid might consort with T cells. In this case, the researchers were wondering why effector CD8+ T cells were about 12 times better at going to inflammation sites around the body than central memory CD8+ cells.Using the same knockout mice, the researchers primed wild type and BLT1-deficient T cells in a test tube with antigens and different cytokines to differentiate them into either effector or central memory cells. Intravital microscopy and other experiments showed that much of effector T cells' superior ability to home to inflamed tissue in the peritoneal area can be explained by their selective response to the lipid LTB4. More than halfway across the country, a husband-wife postdoctoral team at National Jewish Medical and Research Center in Denver was experimenting with CD8+ cells and mast cells. Using von Andrian's T cell differentiation method, first author Vanessa Ott and last author Bradley Swanson found that many more effector T cells than central memory T cells migrated toward activated mast cells. Transcriptional profiling in a microarray analysis revealed substantially more lipid receptor BLT1 mRNA on the effector cells. Additional assays with the lipid alone proved the point. Swanson invited von Andrian to give a talk in Denver, and when they compared notes on their similar results, they decided to publish together. "The three papers fit together very nicely," said Luster, director of the MGH Center for Immunology and Inflammatory Diseases and chief of the Division of Rheumatology, Allergy and Immunology at MGH. "Putting the studies together, it appears that early mast cell activation by IgE induces the recruitment of the first effector T cell into tissue that then would amplify the tissue response through the release of effector cytokines and chemokines." --Carol Cruzan Morton |
