Histologic image of the healthy mouse intestine where the mucosal immune system must remain tolerant to trillions of beneficial microbes, termed the microbiota. Image provided by Dr. Gregory F. Sonnenberg
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.
The discovery, reported Sept. 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.
“As part of this study, we define a novel pathway that drives immune tolerance to microbiota in the gastrointestinal tract,” said senior author Dr. Gregory F. 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. “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.”
Drs. Mengze Lyu and Gregory Sonnenberg
Scientists have long known that trillions of bacteria, fungi, and other microbes dwell symbiotically in the intestines of mammals. The mechanism by which the immune system normally tolerates these “beneficial” gut microbes, instead of attacking them, has not been well understood. But there is evidence that this tolerance breaks down in IBD, leading to harmful flareups of gut inflammation. 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.
In the study, Dr. Sonnenberg and colleagues, including lead author Dr. 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. 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. The dominant immune cell types in these tissues, they found, were T cells and ILC3s. 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.
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. To continue reading, please click here.