Critical Role for the Microbiota in CX 3 CR1 + Intestinal Mononuclear Phagocyte Regulation of Intestinal T Cell Responses

• Published in: Immunity (Cambridge, Mass.) Mass.), 2018-07, Vol.49 (1), p.151
• Main Authors: Kim, Myunghoo, Galan, Carolina, Hill, Andrea A, Wu, Wan-Jung, Fehlner-Peach, Hannah, Song, Hyo Won, Schady, Deborah, Bettini, Matthew L, Simpson, Kenneth W, Longman, Randy S, Littman, Dan R, Diehl, Gretchen E
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics; Antigen Presentation; Antigen-presenting cells; Antigens; Bacteria; Bacterial Adhesion - immunology; Colonization; CX3C Chemokine Receptor 1 - metabolism; CX3CR1 protein; Disease; Disease Models, Animal; Epithelium; Experiments; Female; Gastrointestinal Microbiome - immunology; Homeostasis; Immune Tolerance; Immunity, Mucosal; Immunoregulation; Infections; Inflammation - immunology; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - immunology; Inflammatory diseases; Interleukin-10 - immunology; Interleukin-10 - metabolism; Intestinal microflora; Intestinal Mucosa - immunology; Intestinal Mucosa - microbiology; Intestine; Lymphocytes; Lymphocytes T; Male; Mice; Microbiota; Microorganisms; Mononuclear Phagocyte System - immunology; Pathology; RAW 264.7 Cells; Regulatory mechanisms (biology); Salmonella; T cell receptors; T-Lymphocytes, Regulatory - immunology; Th1 Cells - immunology; Ulcers; Variance analysis
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.05.009

The intestinal barrier is vulnerable to damage by microbiota-induced inflammation that is normally restrained through mechanisms promoting homeostasis. Such disruptions contribute to autoimmune and inflammatory diseases including inflammatory bowel disease. We identified a regulatory loop whereby, in the presence of the normal microbiota, intestinal antigen-presenting cells (APCs) expressing the chemokine receptor CX CR1 reduced expansion of intestinal microbe-specific T helper 1 (Th1) cells and promoted generation of regulatory T cells responsive to food antigens and the microbiota itself. We identified that disruption of the microbiota resulted in CX CR1 APC-dependent inflammatory Th1 cell responses with increased pathology after pathogen infection. Colonization with microbes that can adhere to the epithelium was able to compensate for intestinal microbiota loss, indicating that although microbial interactions with the epithelium can be pathogenic, they can also activate homeostatic regulatory mechanisms. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes tissue homeostasis.