Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110Α and p110Δ are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110Δ PI3K in normal or pathological immune responses is well established, yet the importance of p110Α subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110Α conditionally deleted in CD4 and CD8 T lymphocytes (p110Α-/-ampersand-flag-changeDelta;T) were used. p110Α-/-ampersand-flag-changeDelta;T 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 p110Α-/-ampersand-flag-changeDelta;T T cells showed enhanced effector function, particularly IFN-ampersand-flag-changegamma; secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110Α-/-ampersand-flag-changeDelta;T cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110Α-/-ampersand-flag-changeDelta;T CD8 T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110Α-/-ampersand-flag-changeDelta;T iTreg cells was diminished. Also, p110Α-/-ampersand-flag-changeDelta;T mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-ampersand-flag-changegamma;, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110Α-/-ampersand-flag-changeDelta;T 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 p110Α-/-ampersand-flag-changeDelta;T mice. Also, IFN-ampersand-flag-changegamma; production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110Α plays a significant role in antigen activation and differentiation of CD4 and CD8 T lymphocytes modulating antitumor immunity.
Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110Α and p110Δ are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110Δ PI3K in normal or pathological immune responses is well established, yet the importance of p110Α subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110Α conditionally deleted in CD4 and CD8 T lymphocytes (p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T) were used. p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T 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 p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T T cells showed enhanced effector function, particularly IFN-ampersand-flag-changegamma; secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T CD8 T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T iTreg cells was diminished. Also, p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-ampersand-flag-changegamma;, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T 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 p110Αampersand-flag-changeminus;/ampersand-flag-changeminus;ampersand-flag-changeDelta;T mice. Also, IFN-ampersand-flag-changegamma; production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110Α plays a significant role in antigen activation and differentiation of CD4 and CD8 T lymphocytes modulating antitumor immunity.
