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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    • "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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    • "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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