"We found an extensive system of immune cells throughout the intestinal tract that take up bacteria and other antigens, giving us a new target for understanding the immune response," says Hans-Christian Reinecker, MD, of the MGH Gastrointestinal Unit, the study's senior author.
The investigation focused on dendritic cells which are found in tissues in direct contact with the external environment, such as the skin, lungs and digestive system. Characterized by long extensions called dendrites, dendritic cells continually sample their environment for bacteria and viruses. When dendritic cells encounter pathogens, they ingest them, break them down and then transport protein fragments to the cellular membrane. On the cells' surface the fragments are displayed to other immune system cells, which will recognize the proteins as antigens to be destroyed.
Exactly how dendritic cells monitor intestinal contents and recognize harmful organisms was unknown, and learning more about that process was a goal of the current study. The researchers conducted several experiments using genetically altered mice in which one or both copies of a gene required for cell migration and dendrite formation was replaced with a gene that produces a fluorescent protein. Examination of the animals' tissues revealed populations of dendritic cells throughout the small intestine in a layer just below the epithelial lining. It previously had been believed that gastrointestinal dendritic cells were few in number and restricted to specialized immune organs called Peyer's patches.
Three-dimensional computer-assisted tissue reconstruction allowed detailed microscopic examination of the intestinal tissues, which showed that dendrites extend from the dendritic cells through the epithelial layer, giving them direct access to intestinal contents. In animals without the gene required for normal dendrite growth – which produces a receptor protein – dendrites formed but did not penetrate the epithelium. Dendritic cells without access to the interior of the intestine were not able to carry out one of their normal functions, taking up the harmless strains of E. coli that normally populate the intestine and transporting them to lymph nodes.
Introduction of disease-causing salmonella bacteria into the gastrointestinal system of both groups of mice revealed that the receptor-negative animals, whose dendritic cells could not effectively sample intestinal contents, were unable to mount an effective immune defense and developed extensive salmonella infection.
"This is a new way for the immune system in the gastrointestinal tract to monitor and interact with the environment," says Reinecker, an assistant professor of Medicine at Harvard Medical School. "Insights into these mechanisms could lead to better understanding of conditions such as Crohn's Disease and ulcerative colitis, intestinal infections and food allergy. Targeting these dendritic cells also could help us develop new types of vaccines. And it's possible that some of the gastrointestinal bacteria and viruses that cause serious illness may co-opt the activity of these cells to enter the body and bypass some immune defenses."
Along with Reinecker, the study's co-authors are first author Jan Hendrik Niess, MD, Stephan Brand, MD, Xiubin Gu, Beth McCormick, PhD, and Jatin Vyas, MD, PhD, of MGH; Limor Landsman, PhD, and Steffen Jung, PhD, of the Weitzmann Institute in Israel; Dan Littman, MD, PhD, of the Howard Hughes Medical Institute and New York University; Marianne Boes, PhD, and Hidde Ploegh, PhD, Harvard Medical School; and James Fox, DVM, Massachusetts Institute of Technology. The research was supported by grants from the National Institutes of Health; the Deutsche Forschungsgemeinschaft; the Crohn's and Colitis Foundation of America and the Howard Hughes Medical Institute.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.
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Science