Original Research ARTICLE
T-cell specific loss of the PI-3 kinase p110α catalytic subunit results in enhanced cytokine production and anti tumor response
- 1Centro Nacional de Microbiología, Instituto de Salud Carlos III, Spain
- 2Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Spain
- 3School of Medicine and Health Sciences, Universidad del Rosario, Colombia
- 4Interdisciplinary Research Center of Autoimmune Diseases (IRCAD) and Department of Health Sciences, Università degli Studi del Piemonte Orientale, Italy
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-/-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-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 anti-tumor immunity.
Keywords: PI3-kinase, PI3-kinase alpha subunit, T-Lymphocytes, CD28 costimulation, Anti-KLH response, Melanoma, Experimental
Received: 13 Oct 2017;
Accepted: 06 Feb 2018.
Edited by:Loretta Tuosto, Sapienza Università di Roma, Italy
Reviewed by:Christopher E. Rudd, University of Cambridge, United Kingdom
Klaus Okkenhaug, University of Cambridge, United Kingdom
Copyright: © 2018 Aragoneses-Fenoll, Ojeda, Montes-Casado, Acosta-Ampudia, Dianzani, Portolés and Rojo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Dr. Pilar Portolés, PHD., Instituto de Salud Carlos III, Centro Nacional de Microbiología, Ctra. Majadahonda-Pozuelo km. 2, Majadahonda, Madrid, 20220, Spain, email@example.com
Dr. José M. Rojo, PHD., Centro de Investigaciones Biológicas (CSIC), Cellular and Molecular Medicine, Ramiro de Maeztu, 9, Madrid, 28040, Madrid, Spain, firstname.lastname@example.org