These RORγt+ Tregs then suppress other T cell responses and enforce tolerance to the microbiota. Much like how immune responses are generated to disease-causing microbes, the ILC3s present pieces of gut-dwelling microbes but this elicited RORγt+ Tregs that specifically recognize these microbes rather than an inflammatory immune response. The researchers next found evidence that ILC3s play an essential role in promoting the RORγt+Treg population in the gut. Withers and his laboratory are key contributors to this study and long-term collaborators of Dr. Withers, professor of immune regulation at the Institute of Immunology and Immunotherapy and the University of Birmingham. “We previously defined key roles for ILC3s in regulating adaptive immunity, but these findings are exciting as they provoke a concept that ILC3s directly interact with Tregs to control immune tolerance in the gut,” said Dr. In close collaboration with researchers at the University of Birmingham, UK, the scientists observed that in lymph node regions called interfollicular zones, ILC3s are in close association with a specific type of T cell, called RORγt+ regulatory T cells (Tregs), which are adapted to dial down inflammation and immune activity to promote tolerance in the gut. The latter are a family of immune cells that represent an innate counterpart of T cells, and work as a first line of defense in mucosal tissues such as the intestines and lungs. The dominant immune cell types in these tissues, they found, were T cells and ILC3s. They focused on cells expressing a transcription factor, RORγt, which are known to drive either inflammation or tolerance in response to microbes that colonize the intestine.
Mengze Lyu, a postdoctoral researcher in the Sonnenberg lab, used single-cell sequencing and fluorescent imaging techniques to delineate immune cells in the mesenteric lymph nodes that drain the intestines of healthy mice. Sonnenberg and colleagues, including lead author Dr. Thus, a detailed understanding of gut immune tolerance could enable the development of powerful new treatments for IBD-a class of diseases that include Crohn’s disease and ulcerative colitis, which affect several million individuals in the United States alone. But there is evidence that this tolerance breaks down in IBD, leading to harmful flareups of gut inflammation. The mechanism by which the immune system normally tolerates these “beneficial” gut microbes, instead of attacking them, has not been well understood. Scientists have long known that trillions of bacteria, fungi, and other microbes dwell symbiotically in the intestines of mammals. “This is a fundamental advance in our understanding of mucosal immunity and may hold the key to understanding what goes wrong when the immune system begins to inappropriately attack microbiota in diseases such as IBD.” Sonnenberg, associate professor of microbiology and immunology in medicine and head of basic research in the Division of Gastroenterology & Hepatology, and a member of the Jill Roberts Institute for Research in Inflammatory Bowel Disease at Weill Cornell Medicine. “As part of this study, we define a novel pathway that drives immune tolerance to microbiota in the gastrointestinal tract,” said senior author Dr. 7 in Nature, illuminates an important aspect of gut health and mucosal immunity-one that may hold the key to better treatments for inflammatory bowel disease (IBD), colon cancer and other chronic disorders. Immune cells called group 3 innate lymphoid cells (ILC3s) play an essential role in establishing tolerance to symbiotic microbes that dwell in the human gastrointestinal tract, according to a study led by researchers at Weill Cornell Medicine.
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