T-cell function is partially maintained in the absence of class IA phosphoinositide 3-kinase signaling

Harvard University, Cambridge, Massachusetts, United States
Blood (Impact Factor: 10.45). 05/2007; 109(7):2894-902. DOI: 10.1182/blood-2006-07-038620
Source: PubMed


The class IA subgroup of phosphoinositide 3-kinase (PI3K) is activated downstream of antigen receptors, costimulatory molecules, and cytokine receptors on lymphocytes. Targeted deletion of individual genes for class IA regulatory subunits severely impairs the development and function of B cells but not T cells. Here we analyze conditional mutant mice in which thymocytes and T cells lack the major class IA regulatory subunits p85alpha, p55alpha, p50alpha, and p85beta. These cells exhibit nearly complete loss of PI3K signaling downstream of the T-cell receptor (TCR) and CD28. Nevertheless, T-cell development is largely unperturbed, and peripheral T cells show only partial impairments in proliferation and cytokine production in vitro. Both genetic and pharmacologic experiments suggest that class IA PI3K signaling plays a limited role in T-cell proliferation driven by TCR/CD28 clustering. In vivo, class IA-deficient T cells provide reduced help to B cells but show normal ability to mediate antiviral immunity. Together these findings provide definitive evidence that class IA PI3K regulatory subunits are essential for a subset of T-cell functions while challenging the notion that this signaling mechanism is a critical mediator of costimulatory signals downstream of CD28.

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    • "In addition to that mice with a knock-in point mutation of p110δ (p110deltaD910A/D910A) have severe defects in T cell receptor signaling and impaired Treg cell function (13–15). The T cell specific class IA PI3K deficient mice do not have defects in thymocyte and in peripheral T cell development, but they do exhibit defective TCR signaling, in vitro proliferation and cytokine production (16, 17). Altogether these findings demonstrate that the PI3K signaling pathway responsible for generation of PtdIns(3,4,5)P3 plays an important role in T cell development and activation and suggest that inositol poly-phosphatases like phosphatase and tensin homolog (PTEN), SHIP1, SHIP2, and INPP4A/B may have an opposing, or in some cases, a facilitating role downstream of PI3K in T lymphocytes. "
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    ABSTRACT: T lymphocytes play a critical role in host defense in all anatomical sites including mucosal surfaces. This not only includes the effector arm of the immune system, but also regulation of immune responses in order to prevent autoimmunity. Genetic targeting of PI3K isoforms suggests that generation of PI(3,4,5)P3 by PI3K plays a critical role in promoting effector T cell responses. Consequently, the 5'- and 3'-inositol poly-phosphatases SHIP1, SHIP2, and phosphatase and tensin homolog capable of targeting PI(3,4,5)P3 are potential genetic determinants of T cell effector functions in vivo. In addition, the 5'-inositol poly-phosphatases SHIP1 and 2 can shunt PI(3,4,5)P3 to the rare but potent signaling phosphoinositide species PI(3,4)P2 and thus these SHIP1/2, and the INPP4A/B enzymes that deplete PI(3,4)P2 may have precise roles in T cell biology to amplify or inhibit effectors of PI3K signaling that are selectively recruited to and activated by PI(3,4)P2. Here we summarize recent genetic and chemical evidence that indicates the inositol poly-phosphatases have important roles in both the effector and regulatory functions of the T cell compartment. In addition, we will discuss future genetic studies that might be undertaken to further elaborate the role of these enzymes in T cell biology as well as potential pharmaceutical manipulation of these enzymes for therapeutic purposes in disease settings where T cell function is a key in vivo target.
    Frontiers in Immunology 09/2013; 4:288. DOI:10.3389/fimmu.2013.00288
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    • "The capacity of these inputs to regulate mTOR activation in T cells is reflected by the ability of 2-deoxyglucose (2-DG) mimicking glucose deprivation, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimicking cellular energy depletion, and n-acetyl leucine (NALA) mimicking amino acid depletion to result in anergy when present during CD3/CD28 stimulation of T cells, analogous to rapamycin treatment (Zheng et al., 2009). The presence of normal energy, amino acids, and normoxia to promote mTOR activation is therefore consistent with the reported preservation of some mTORC1 activity in the r1ΔT/r2n mice (Deane et al., 2007). This relative increase in mTORC1 activity over mTORC2 activity in these mice supports the observed relative preservation of Th1 cytokine production over Th2 cytokines, analogous to the Rictor deficient T cell mice noted above (Lee et al., 2010; Delgoffe et al., 2011). "
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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.
    Frontiers in Immunology 10/2012; 3:312. DOI:10.3389/fimmu.2012.00312
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    • "BCR-dependent mTORC1 activation is PI3K-dependent whereas basal and LPS-dependent mTORC1 activity is partly PI3K-independent. Similarly, mTORC1 activity is sustained in activated T cells lacking detectable PI3K/Akt activity (Deane et al., 2007). Other Akt-independent inputs are likely to regulate downstream mTORC1 substrates in lymphocytes, as has been shown for the S6 ribosomal protein in CD8 T cells (Salmond et al., 2009). "
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    ABSTRACT: Activation of phosphoinositide 3-kinase (PI3K) is required for B cell proliferation and survival. PI3K signaling also controls key aspects of B cell differentiation. Upon engagement of the B cell receptor (BCR), PI3K activation promotes Ca(2+) mobilization and activation of NFκB-dependent transcription, events which are essential for B cell proliferation. PI3K also initiates a distinct signaling pathway involving the Akt and mTOR serine/threonine kinases. It has been generally assumed that activation of Akt and mTOR downstream of PI3K is essential for B cell function. However, Akt and mTOR have complex roles in B cell fate decisions and suppression of this pathway can enhance certain B cell responses while repressing others. In this review we will discuss genetic and pharmacological studies of Akt and mTOR function in normal B cells, and in malignancies of B cell origin.
    Frontiers in Immunology 08/2012; 3:228. DOI:10.3389/fimmu.2012.00228
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