Innate PI3K p110δ Regulates Th1/Th17 Development and Microbiota-Dependent Colitis

• Published in: The Journal of immunology (1950) Vol. 192; no. 8; pp. 3958 - 3968
• Main Authors: Steinbach, Erin C, Kobayashi, Taku, Russo, Steven M, Sheikh, Shehzad Z, Gipson, Gregory R, Kennedy, Samantha T, Uno, Jennifer K, Mishima, Yoshiyuki, Borst, Luke B, Liu, Bo, Herfarth, Hans, Ting, Jenny P Y, Sartor, R Balfour, Plevy, Scott E
• Format: Journal Article
• Language: English
• Published: United States 15.04.2014
• Subjects: Animals; Antigen-Presenting Cells - immunology; Antigen-Presenting Cells - metabolism; Class Ia Phosphatidylinositol 3-Kinase - genetics; Class Ia Phosphatidylinositol 3-Kinase - metabolism; Colitis - genetics; Colitis - immunology; Colitis - metabolism; Colitis - microbiology; Colitis - pathology; Cytokines - biosynthesis; Disease Models, Animal; Gene Expression Regulation; Immunity, Innate - genetics; Interleukin-10 - biosynthesis; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - microbiology; Intestinal Mucosa - pathology; Macrophages - immunology; Macrophages - metabolism; Male; Mice; Mice, Knockout; Microbiota; Th1 Cells - immunology; Th1 Cells - metabolism; Th17 Cells - immunology; Th17 Cells - metabolism; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1301533

The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δKD) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δKD mice through increased IL-12 and IL-23 expression. In this study, we show that the enteric microbiota is required for colitis development in germfree p110δKD mice. Colonic tissue and macrophages from p110δKD mice produce significantly less IL-10 compared with wild-type mice. p110δKD APCs cocultured with naive CD4+ Ag-specific T cells also produce significantly less IL-10 and induce more IFN-γ– and IL-17A–producing CD4+ T cells compared with wild-type APCs. Illustrating the importance of APC–T cell interactions in colitis pathogenesis in vivo, Rag1−/−/p110δKD mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1−/− mice. However, CD4+CD45RBhigh/low T cell Rag1−/−/p110δKD recipient mice develop severe colitis with increased percentages of IFN-γ– and IL-17A–producing lamina propria CD3+CD4+ T cells compared with Rag1−/− recipient mice. Intestinal tissue samples from patients with Crohn’s disease reveal significantly lower expression of PIK3CD compared with intestinal samples from non–inflammatory bowel disease control subjects (p < 0.05). PIK3CD expression inversely correlates with the ratio of IL12B:IL10 expression. In conclusion, the PI3K subunit p110δ controls homeostatic APC–T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110δ expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.