Group 3 innate cells (red staining with green staining in the center) are found in between B cell follicles (grey staining) where immune responses take place in gut-associated lymph nodes. Picture courtesy of Dr. David Withers.
The intestinal mucosal barrier surface is constantly exposed to various stimuli such as food antigens, beneficial microbes, and infectious pathogens. Immune cells in the intestine and associated lymphoid tissues play a critical role in maintaining barrier function and intestinal homeostasis.
A new study by Dr. David Artis and his colleagues at Weill Cornell Medicine, identifies that the accumulation and function of group 3 innate lymphoid cells, a key immune cell population that limits bacterial infections in the intestine, are regulated by G protein-coupled receptor 183 (GPR183) and its ligand oxysterol produced by stromal cells. The study is co-authored by multiple investigators including Dr. Gregory F. Sonnenberg (Weill Cornell Medicine) and Dr. David Withers (University of Birmingham) and was published on June 26, 2018 in Cell Reports.
“Group 3 innate lymphoid cells are enriched in mucosal barrier surfaces and lymphoid tissues, and are a key immune cell in maintaining intestinal health against bacterial infections,” said Dr. Artis, director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor of Immunology at Weill Cornell Medicine. “However, the molecular mechanisms that control how group 3 innate lymphoid cells are distributed in the intestine and lymphoid tissues and how their functions are controlled during bacterial infection are not fully understood.”
For their study, Dr. Artis and his colleagues focused on a G protein-coupled receptor 183 (GPR183, also known as EBI2). GPR183 is highly expressed on lymphocytes in spleen and lymph nodes and controls cell migration to achieve efficient antibody responses and CD4+ T cell responses. Dr. Artis and his team found that group 3 innate lymphoid cells, not only in gut-draining lymph nodes but also in the intestine, highly expressed GPR183 that controls the distribution of group 3 innate lymphoid cells in these tissues. Furthermore, GPR183 ligand, 7α,25-dihydroxycholesterol was produced by gut stromal cells, supporting a role for these structural cells in controlling the location and functional potential of group 3 innate lymphoid cells.
To examine the role of GPR183 and its ligand, Dr. Artis and his team employed mice that lack the receptor and the ligand-producing enzyme CH25H and found disorganized accumulation of ILC3s in the gut-draining lymph nodes and reduced ILC3 accumulation in the intestine in the absence of GPR183 or its ligand. “Considering the regulation of lymphocytes by ILC3s in the lymphoid organs and the importance of immune cell localization in these organs, it is important to know how ILC3 localization is controlled in the lymph nodes. And our findings may provide new targets to control immune responses in the lymphoid organs,” said Dr. Coco Chu, a postdoctoral associate in Dr. Artis’ laboratory and a co-first author of the study.
“We then wanted to know if this GPR183 is essential for a protection against gastrointestinal pathogens,” said Dr. Saya Moriyama, a postdoctoral associate in Dr. Artis’ laboratory and another co-first author of the study. To examine this, Dr. Artis and his colleagues used Citrobacter rodentium infection, which is a gastrointestinal pathogen of mice that has several pathogenic similarities with clinically important human gastrointestinal pathogens. “And we found that GPR183 promotes accumulation of cytokine-producing group 3 innate lymphoid cells in the gut and is required for protection against this infection.,” she added.
GPR183 plays important roles in regulating the distribution and function of ILC3s in both lymphoid and non-lymphoid tissue so GPR183 and its oxysterol ligand-producing pathway could be potential therapeutic targets for controlling and regulating ILC3 functions in multiple infectious and inflammatory diseases.
This study was supported by grants from the National Institutes of Health (DP5OD012116, AI123368, DK110262, AI095608, AI074878, AI083480, AI095466, AI095608, AI102942, AI097333 and AI106697), the German Research Foundation (KL 2963/1-1), the Novo Nordic Foundation (14052), the Jill Roberts Institute, the Wellcome Trust (Senior Research Fellowship 110199/Z/15/Z), Cure for IBD, the Crohn’s and Colitis Foundation of America, the Searle Scholars Program, an American Asthma Foundation Scholar Award, the Burroughs Wellcome Fund. Dr. Moriyama is also the Japanese Society for the Promotion of Science Overseas Research Fellow.