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PI3Kγ kinase activity is required for optimal T‐cell activation and differentiation
Author(s) -
Ladygidia,
Gottipati Sridevi,
Ngo Karen,
Castro Glenda,
Ma JingYing,
Banie Homayon,
Rao Tadimeti S.,
FungLeung WaiPing
Publication year - 2013
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.201343812
Subject(s) - pi3k/akt/mtor pathway , biology , cd28 , microbiology and biotechnology , t cell , kinase , protein kinase b , phosphatidylinositol , immune system , signal transduction , immunology
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 KD/KD ) mice expressing the kinase‐inactive PI3Kγ protein. We show that CD4 + and CD8 + T cells from PI3Kγ KD/KD 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 KD/KD 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 KD/KD CD4 + T cells displayed compromised differentiation toward Th1, Th2, Th17, and induced Treg cells. PI3Kγ KD/KD 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.