| First Author | Ladygina N | Year | 2013 |
| Journal | Eur J Immunol | Volume | 43 |
| Issue | 12 | Pages | 3183-96 |
| PubMed ID | 24030559 | Mgi Jnum | J:205926 |
| Mgi Id | MGI:5547438 | Doi | 10.1002/eji.201343812 |
| Citation | Ladygina N, et al. (2013) PI3Kgamma kinase activity is required for optimal T-cell activation and differentiation. Eur J Immunol 43(12):3183-96 |
| abstractText | Phosphatidylinositol-3-kinase gamma (PI3Kgamma) is a leukocyte-specific lipid kinase with signaling function downstream of G protein-coupled receptors to regulate cell trafficking, but its role in T cells remains unclear. To investigate the requirement of PI3Kgamma kinase activity in T-cell function, we studied T cells from PI3Kgamma kinase-dead knock-in (PI3Kgamma(KD/KD)) mice expressing the kinase-inactive PI3Kgamma protein. We show that CD4(+) and CD8(+) T cells from PI3Kgamma(KD/KD) mice exhibit impaired TCR/CD28-mediated activation that could not be rescued by exogenous IL-2. The defects in proliferation and cytokine production were also evident in naive and memory T cells. Analysis of signaling events in activated PI3Kgamma(KD/KD) T cells revealed a reduction in phosphorylation of protein kinase B (AKT) and ERK1/2, a decrease in lipid raft formation, and a delay in cell cycle progression. Furthermore, PI3Kgamma(KD/KD) CD4(+) T cells displayed compromised differentiation toward Th1, Th2, Th17, and induced Treg cells. PI3Kgamma(KD/KD) mice also exhibited an impaired response to immunization and a reduced delayed-type hypersensitivity to Ag challenge. These findings indicate that PI3Kgamma kinase activity is required for optimal T-cell activation and differentiation, as well as for mounting an efficient T cell-mediated immune response. The results suggest that PI3Kgamma kinase inhibitors could be beneficial in reducing the undesirable immune response in autoimmune diseases. |
