T-Cell-specific loss of the PI-3-linase p110? catalytic subunit results in enhanced cytokine production and antitumor response

Class IA phosphatidylinositol 3-kinase (PI3K) catalytic subunits p110? and p110? are targets in cancer therapy expressed at high levels in T lymphocytes. The role of p110? PI3K in normal or pathological immune responses is well established, yet the importance of p110? subunits in T cell-dependent immune responses is not clear. To address this problem, mice with p110? conditionally deleted in CD4+ and CD8+ T lymphocytes (p110??/??T) were used. p110??/??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+ p110??/??T T cells showed enhanced effector function, particularly IFN-? secretion, T-bet induction, and Akt, Erk, or P38 activation. Tfh derived from p110??/??T cells also have enhanced responses when compared to normal mice, and IL-2 expanded p110??/??T CD8+ T cells had enhanced levels of LAMP-1 and Granzyme B. By contrast, the expansion of p110??/??T iTreg cells was diminished. Also, p110??/??T mice had enhanced anti-keyhole limpet hemocyanin (KLH) IFN-?, or IL-4 responses and IgG1 and IgG2b anti-KLH antibodies, using CFA or Alum as adjuvant, respectively. When compared to WT mice, p110??/??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 p110??/??T mice. Also, IFN-? production in tumor antigen-activated spleen cells was enhanced. Thus, PI3K p110? plays a significant role in antigen activation and differentiation of CD4+ and CD8+ T lymphocytes modulating antitumor immunity.

• Fecha de publicación: 2018
• Institución: Universidad del Rosario
• Repositorio: Repositorio EdocUR - U. Rosario
• Idioma: eng
• OAI Identifier: oai:repository.urosario.edu.co:10336/25984
• Acceso en línea: https://doi.org/10.3389/fimmu.2018.00332; https://repository.urosario.edu.co/handle/10336/25984
• Palabra clave: PI3K; PI3-kinase alpha subunit; T lymphocytes; CD28 costimulation; Anti-KLH response; Melanoma
• License: Abierto (Texto Completo)