T-cell-specific loss of the PI-3-kinase p110α catalytic subunit results in enhanced cytokine production and antitumor response

Laura Aragoneses-Fenoll, Gloria Ojeda, María Montes-Casado, Yeny Acosta-Ampudia, Umberto Dianzani, Pilar Portolés, José M. Rojo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110α and p110d are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110d 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-/-ΔT) were used. p110α-/-ΔT 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-/-ΔT T cells showed enhanced effector function, particularly IFN-γ secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110α-/-ΔT cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110α-/-ΔT CD8+ T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110α-/-ΔT iTreg cells was diminished. Also, p110α-/-ΔT mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-γ, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110α-/-ΔT 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-/-ΔT mice. Also, IFN-γ 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.

Original languageEnglish (US)
Article number332
JournalFrontiers in Immunology
Volume9
Issue numberFEB
DOIs
StatePublished - Feb 27 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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