PI3Kγ kinase activity is required for optimal T‐cell activation and differentiation. (9th October 2013)

• Record Type: Journal Article
• Authors: Ladygina, Nadia; Gottipati, Sridevi; Ngo, Karen; Castro, Glenda; Ma, Jing‐Ying; Banie, Homayon; Rao, Tadimeti S.; Fung‐Leung, Wai‐Ping
• Is Part Of: European journal of immunology. Volume 43:issue 12(2013:Dec.)
• Page Start: 3183
• Page End: 3196
• Publication Date: 2013-10-09
• Subjects: Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201343812
• Languages: English
• ISSNs: 0014-2980

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Phosphatidylinositol‐3‐kinase gamma (PI3Kγ) is a leukocyte‐specific lipid kinase with signaling function downstream of G protein‐coupled receptors to regulate cell trafficking, but its role in T cells remains unclear. To investigate the requirement of PI3Kγ kinase activity in T‐cell function, we studied T cells from PI3Kγ kinase‐dead knock‐in (PI3Kγ<sup>KD/KD</sup>) mice expressing the kinase‐inactive PI3Kγ protein. We show that CD4<sup>+</sup> and CD8<sup>+</sup> T cells from PI3Kγ<sup>KD/KD</sup> mice exhibit impaired TCR/CD28‐mediated activation that could not be rescued by exogenous IL‐2. The defects in proliferation and cytokine production were also evident in naïve and memory T cells. Analysis of signaling events in activated PI3Kγ<sup>KD/KD</sup> T cells revealed a reduction in phosphorylation of protein kinase B (AKT) and ERK1/2, a decrease in lipid raft formation, and a delay in cell cycle progression. Furthermore, PI3Kγ<sup>KD/KD</sup> CD4<sup>+</sup> T cells displayed compromised differentiation toward Th1, Th2, Th17, and induced Treg cells. PI3Kγ<sup>KD/KD</sup> mice also exhibited an impaired response to immunization and a reduced delayed‐type hypersensitivity to Ag challenge. These findings indicate that PI3Kγ kinase activity is required for optimal T‐cell activation and differentiation, as well as for mounting an efficient T cell‐mediated immune response. The results suggest that PI3Kγ kinase inhibitors could be beneficial in reducing the undesirable immune response in autoimmune diseases.</p> </abstract>