The p110 isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites

Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Journal of Leukocyte Biology (Impact Factor: 4.29). 09/2008; 84(3):814-23. DOI: 10.1189/jlb.0807561
Source: PubMed


The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110gamma isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110gamma does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Naïve p110gamma(-/-) CD4 lymphocytes are phenotypically identical to their wild-type (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110gamma-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110gamma-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110gamma-deficient CD4 T cells express P-selectin ligand, beta2 integrin, beta1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired F-actin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110gamma regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.

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Available from: Yoji Shimizu, Sep 02, 2015
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    • "Despite the controversy surrounding whether p110γ is coupled directly to TCR or CD28, it is clear that loss of p110γ impacts T cell effector function. Both CD4 and CD8 p110γ −/− T cells have defective effector T cell migration in vivo that correlates with impaired migratory responses to chemokines in vitro (Martin et al., 2008; Thomas et al., 2008). Expression of granzyme B and IFN-γ appears normal in p110γ −/− CD8 effector T cells generated in vivo by antigen exposure (Martin et al., 2008). "
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    ABSTRACT: The mechanistic target of rapamycin (mTOR) is emerging as playing a central role in regulating T cell activation, differentiation, and function. mTOR integrates diverse signals from the immune microenvironment to shape the outcome of T cell receptor (TCR) antigen recognition. Phosphatidylinositol 3-kinase (PI3K) enzymes are critical mediators of T cell activation through their generation of the second messenger phosphatidylinositol (3,4,5) triphosphate (PIP3). Indeed, PIP3 generation results in the activation of Protein Kinase B (PKB, also known as AKT), a key activator of mTOR. However, recent genetic studies have demonstrated inconsistencies between PI3K disruption and loss of mTOR expression with regard to the regulation of effector and regulatory T cell homeostasis and function. In this review, we focus on how PI3K activation directs mature CD4 T cell activation and effector function by pathways dependent on and independent of mTOR signaling. Importantly, what has become clear is that targeting both mTOR-dependent and mTOR-independent PI3K-induced signaling distally affords the opportunity for more selective regulation of T cell differentiation and function.
    Preview · Article · Oct 2012 · Frontiers in Immunology
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    • "However, conflicting data suggesting that TCR signalling is PI3Kγ independent also exist. Normal T cell activation was reported in pik3cg−/− mice during adjuvant-induced arthritis [42] and equivalent naïve CD4+ T cell activation was reported between WT and pik3cg−/− T cells induced both in vitro and in vivo using TCR-transgenic mice [38] and in a related study by Berod et al. [43]. It seems likely that these apparent discrepancies are due to differences in the T cell activation systems and different read-outs of activation that have been utilised between these different studies. "
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    ABSTRACT: The class IB phosphoinositide 3-kinase gamma enzyme complex (PI3Kγ) functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg(-/-) mice and a selective PI3Kγ inhibitor, we show that PI3Kγ promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg(-/-) mice, EAE is markedly suppressed and fewer leukocytes including CD4(+) and CD8(+) T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4(+) T cell priming in secondary lymphoid organs is reduced in pik3cg(-/-) mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110γ. Together, this results in suppressed autoreactive T cell responses in pik3cg(-/-) mice, with more CD4(+) T cells undergoing apoptosis and fewer cytokine-producing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kγ inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kγ may be useful therapeutics for MS.
    Preview · Article · Sep 2012 · PLoS ONE
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    • "Consequently, p110δ controlled proliferation, cytokine production , differentiation into helper T cells (Th) subsets, and trafficking (Okkenhaug et al., 2002, 2006; Nashed et al., 2007; Garcon et al., 2008; Jarmin et al., 2008; Sinclair et al., 2008; Liu et al., 2009; Rolf et al., 2010; Soond et al., 2010; Macintyre et al., 2011). The p110γ isoform of PI3K is required for migration toward inflammatory chemokines and memory T cell survival (Barber et al., 2006; Martin et al., 2008; Thomas et al., 2008). Conversely, T cells lacking Pten are hypersensitive to TCR and IL-2 signaling leading to augmented Th cell functions, autoimmunity, and leukemia (Suzuki et al., 2001; Buckler et al., 2006; Liu et al., 2010; Guo et al., 2011; Soond et al., 2012). "
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    ABSTRACT: Regulatory T cells (Tregs) prevent autoimmunity and inflammation by suppressing the activation of other T cells and antigen presenting cells. The role of phosphoinositide 3-kinase (PI3K) signaling in Treg is controversial. Some studies suggest that inhibition of the PI3K pathway is essential for the development of Tregs whereas other studies have shown reduced Treg numbers and function when PI3K activity is suppressed. Here we attempt to reconcile the different studies that have explored PI3K and the downstream effectors Akt, Foxo, and mTOR in regulatory T cell development and function and discuss the implications for health and therapeutic intervention.
    Full-text · Article · Aug 2012 · Frontiers in Immunology
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