| First Author | Aragoneses-Fenoll L | Year | 2018 |
| Journal | Front Immunol | Volume | 9 |
| Pages | 332 | PubMed ID | 29535720 |
| Mgi Jnum | J:339391 | Mgi Id | MGI:6823151 |
| Doi | 10.3389/fimmu.2018.00332 | Citation | Aragoneses-Fenoll L, et al. (2018) T-Cell-Specific Loss of the PI-3-Kinase p110alpha Catalytic Subunit Results in Enhanced Cytokine Production and Antitumor Response. Front Immunol 9:332 |
| abstractText | Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110alpha and p110delta are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110delta PI3K in normal or pathological immune responses is well established, yet the importance of p110alpha subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110alpha conditionally deleted in CD4(+) and CD8(+) T lymphocytes (p110alpha(-/-)DeltaT) were used. p110alpha(-/-)DeltaT mice show normal development of T cell subsets, but slightly reduced numbers of CD4(+) T cells in the spleen. "In vitro," TCR/CD3 plus CD28 activation of naive CD4(+) and CD8(+) p110alpha(-/-)DeltaT T cells showed enhanced effector function, particularly IFN-gamma secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110alpha(-/-)DeltaT cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110alpha(-/-)DeltaT CD8(+) T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110alpha(-/-)DeltaT iTreg cells was diminished. Also, p110alpha(-/-)DeltaT mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-gamma, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110alpha(-/-)DeltaT mice inoculated with B16.F10 melanoma showed delayed tumor progression. The percentage of CD8(+) T lymphocytes was higher and the percentage of Treg cells lower in the spleen of tumor-bearing p110alpha(-/-)DeltaT mice. Also, IFN-gamma production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110alpha plays a significant role in antigen activation and differentiation of CD4(+) and CD8(+) T lymphocytes modulating antitumor immunity. |
