Innate PI3K p110δ Regulates Th1/Th17 Development and Microbiota-Dependent Colitis
- 15 April 2014
- journal article
- Published by The American Association of Immunologists
- Vol. 192 (8), 3958-3968
- https://doi.org/10.4049/jimmunol.1301533
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 (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.Keywords
This publication has 43 references indexed in Scilit:
- Dynamics of the Phosphoinositide 3-Kinase p110δ Interaction with p85α and Membranes Reveals Aspects of Regulation Distinct from p110αStructure, 2011
- The role of the macrophage in sentinel responses in intestinal immunityCurrent Opinion in Gastroenterology, 2010
- Altered Macrophage Function Contributes to Colitis in Mice Defective in the Phosphoinositide-3 Kinase Subunit p110δGastroenterology, 2010
- Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretionThe Journal of cell biology, 2010
- TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cellsThe Journal of Experimental Medicine, 2009
- Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesisNature Genetics, 2007
- The Wiskott-Aldrich syndrome protein is required for the function of CD4+CD25+Foxp3+ regulatory T cellsThe Journal of Experimental Medicine, 2007
- S6K1 Regulates GSK3 under Conditions of mTOR-Dependent Feedback Inhibition of AktMolecular Cell, 2006
- Carbon monoxide ameliorates chronic murine colitis through a heme oxygenase 1–dependent pathwayThe Journal of Experimental Medicine, 2005
- Negative regulation of Toll-like receptor-mediated immune responsesNature Reviews Immunology, 2005