title: Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.
abstract: The p110δ subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110δ subunit (p110δ(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110δ(KD) 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 p110δ(KD) mice. Colonic tissue and macrophages from p110δ(KD) mice produce significantly less IL-10 compared with wild-type mice. p110δ(KD) 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(-/-)/p110δ(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110δ(KD) recipient mice develop severe colitis with increased percentages of IFN-γ- and IL-17A-producing lamina propria CD3+D4+ 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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599;
authors.forename: Erin C
authors.initials: EC
authors.lastname: Steinbach
authors.forename: Taku
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Steven M
authors.initials: SM
authors.lastname: Russo
authors.forename: Shehzad Z
authors.initials: SZ
authors.lastname: Sheikh
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Gipson
authors.forename: Samantha T
authors.initials: ST
authors.lastname: Kennedy
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Uno
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Mishima
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Hans
authors.initials: H
authors.lastname: Herfarth
authors.forename: Jenny P Y
authors.initials: JP
authors.lastname: Ting
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Scott E
authors.initials: SE
authors.lastname: Plevy
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D007113:Immunity, Innate / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D064307:Microbiota; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D016753:Interleukin-10; D058543:Class Ia Phosphatidylinositol 3-Kinase; D058570:TOR Serine-Threonine Kinases