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

The p110 delta subunit of class I-A PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110 delta subunit (p110 delta(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/ Th17 cytokine bias in p110 delta(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 p110 delta(KD) mice. Colonic tissue and macrophages from p110d KD mice produce significantly less IL-10 compared with wild-type mice. p110 delta(KD) APCs cocultured with naive CD4(+) Ag-specific T cells also produce significantly less IL-10 and induce more IFN-gamma-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(-/)-/p110 delta(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1 2/ 2 mice. However, CD4(+)CD45RB(high/low) T cell Rag1(-/-2)/p110 delta(KD) recipient mice develop severe colitis with increased percentages of IFN-gamma-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 p110 delta controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/ 23. Defects in p110 delta expression and/ or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies.