| First Author | Steinbach EC | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 8 | Pages | 3958-68 |
| PubMed ID | 24634494 | Mgi Jnum | J:210009 |
| Mgi Id | MGI:5569228 | Doi | 10.4049/jimmunol.1301533 |
| Citation | Steinbach EC, et al. (2014) Innate PI3K p110delta regulates Th1/Th17 development and microbiota-dependent colitis. J Immunol 192(8):3958-68 |
| abstractText | The p110delta subunit of class IA PI3K modulates signaling in innate immune cells. We previously demonstrated that mice harboring a kinase-dead p110delta subunit (p110delta(KD)) develop spontaneous colitis. Macrophages contributed to the Th1/Th17 cytokine bias in p110delta(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 p110delta(KD) mice. Colonic tissue and macrophages from p110delta(KD) mice produce significantly less IL-10 compared with wild-type mice. p110delta(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(-/-)/p110delta(KD) mice develop mild colonic inflammation and produced more colonic IL-12p40 compared with Rag1(-/-) mice. However, CD4+ CD45RB(high/low) T cell Rag1(-/-)/p110delta(KD) recipient mice develop severe colitis with increased percentages of IFN-gamma- 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 p110delta controls homeostatic APC-T cell interactions by altering the balance between IL-10 and IL-12/23. Defects in p110delta expression and/or function may underlie the pathogenesis of human inflammatory bowel disease and lead to new therapeutic strategies. |
