A Late, Prolonged Activation of the Phosphatidylinositol 3-Kinase Pathway Is Required for T Cell Proliferation

Lali, Ferdinand V.; Crawley, James B.; McCulloch, Derek; Foxwell, Brian M. J.

doi:10.4049/jimmunol.172.6.3527

Cited by 38 publications

(36 citation statements)

References 41 publications

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“…Tritiated thymidine incorporation into T-cells stimulated with anti-CD3 and anti-CD28 were more sensitive to LY294002 (IC 50 ¼ 0.625 mM) than tritiated thymidine incorporation into T-cells stimulated with anti-CD3 alone (IC 50 ¼ 2 mM). Results from similar systems have reported an IC 50 for LY294002 inhibition of CD3-induced mouse T-cell proliferation as approximately 0.5 mM (Haeryfar & Hoskin, 2001) and for IL-7-induced human T-cell proliferation as less than 5 mM (Lali et al, 2004). These different IC 50 values reflect alternative cell types and stimuli, but may also reflect varied dependencies on PI3K for cell survival and proliferation.…”

Section: Discussionmentioning

confidence: 96%

LY294002 and rapamycin co‐operate to inhibit T‐cell proliferation

Breslin

White

Shore

et al. 2005

British J Pharmacology

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1 T-cell proliferation is critical for mounting an effective adaptive immune response. It is regulated by signals through the T-cell receptor, through co-stimulation and through cytokines such as interleukin-2 (IL-2). Phosphatidylinositol 3-kinase (PI3K) lies downstream of each of these pathways and has been directly implicated in the regulation of lymphocyte proliferation. 2 In this study, we have shown that PI3K regulates cyclin D2 and cyclin D3, the first cell cycle proteins induced in T-cell proliferation, transcriptionally and post-transcriptionally. In T-lymphoblasts, LY294002, a PI3K inhibitor, prevents the induction of both D-type cyclin mRNA and protein, while rapamycin inhibits the induction of protein. Rapamycin inhibits mammalian target of rapamycin (mTOR), which lies downstream of PI3K. 3 Furthermore, our data show that the combination of LY294002 and rapamycin results in a cooperative inhibition of T-cell proliferation. This co-operation occurs in Kit225 cells stimulated with IL-2, and also in resting peripheral blood lymphocytes stimulated with antibodies to the T-cell receptor in the presence and absence of antibodies to CD28. 4 These data indicate that PI3K regulates T-cell proliferation in response to diverse stimuli, and suggest that combinations of inhibitors, perhaps isoform-selective, may be useful as alternative immunosuppressive therapies.

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Section: Discussionmentioning

confidence: 96%

LY294002 and rapamycin co‐operate to inhibit T‐cell proliferation

Breslin

White

Shore

et al. 2005

British J Pharmacology

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“…In either case the prolonged occupancy of these surface receptors is likely to develop sequential waves of intracellular signaling events able to sustain optimal cell division. This effect was originally proven to occur in response to growth factors such as PDGF (44,45), and recently proposed for IL-2 and IL-7 (46).…”

Section: Discussionmentioning

confidence: 99%

Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin

Colombetti

Basso

Mueller

et al. 2006

The Journal of Immunology

120

121

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Proliferation of Ag-specific T cells is central to the development of protective immunity. The concomitant stimulation of the TCR and CD28 programs resting T cells to IL-2-driven clonal expansion. We report that a prolonged occupancy of the TCR and CD28 bypasses the need for autocrine IL-2 secretion and sustains IL-2-independent lymphocyte proliferation. In contrast, a short engagement of the TCR and CD28 only drives the expansion of cells capable of IL-2 production. TCR/CD28- and IL-2-driven proliferation revealed a different requirement for PI3K and for the mammalian target of rapamycin (mTOR). Thus, both PI3K and mTOR activities were needed for T cells to proliferate to TCR/CD28-initiated stimuli and for optimal cyclin E expression. In contrast, either PI3K or mTOR were sufficient for IL-2-driven cell proliferation as they independently mediated cyclin E induction. Interestingly, rapamycin delayed cell cycle entry of IL-2-sufficient T cells, but did not prevent their expansion. Together, our findings indicate that the TCR, CD28, and IL-2 independently control T cell proliferation via distinct signaling pathways involving PI3K and mTOR. These data suggest that Ag persistence and the availability of costimulatory signals and of autocrine and paracrine growth factors individually shape T lymphocyte expansion in vivo.

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“…Several in vitro studies of T cell proliferation have previously implicated the persistent activation of CD28, PI3K, Akt/protein kinase B, and mammalian target of rapamycin, in addition to the TCR, in the maintenance of an optimal rate of cell growth and division at late times during the proliferative response (14,15,44). Furthermore, Akt/protein kinase B transgenic T cells demonstrate a more durable proliferative response (45).…”

Section: Discussionmentioning

confidence: 99%

Proliferating CD4+ T Cells Undergo Immediate Growth Arrest upon Cessation of TCR Signaling In Vivo

Yarke

Dalheimer

Zhang

et al. 2008

The Journal of Immunology

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To investigate the role of TCR signaling in the exit of CD4+ T cells from cell cycle, we took advantage of a low frequency TEa T cell adoptive transfer technique as well as the Y-Ae mAb to interrupt Ag/MHC recognition before the completion of clonal expansion. Termination of TCR signaling after 36 h of Ag exposure caused an immediate reduction in cell size and deceleration of G1—>SG2M phase cell cycle progression. As a consequence, clonal expansion in the absence of durable TCR signaling decreased by two-thirds. Thus, CD4+ T cells scan for the presence Ag throughout their clonal expansion response, and continuously adjust their rate of cell growth and G1—>S phase transition to match their intensity of TCR signaling.

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A Late, Prolonged Activation of the Phosphatidylinositol 3-Kinase Pathway Is Required for T Cell Proliferation

Cited by 38 publications

References 41 publications

LY294002 and rapamycin co‐operate to inhibit T‐cell proliferation

LY294002 and rapamycin co‐operate to inhibit T‐cell proliferation

Prolonged TCR/CD28 Engagement Drives IL-2-Independent T Cell Clonal Expansion through Signaling Mediated by the Mammalian Target of Rapamycin

Proliferating CD4+ T Cells Undergo Immediate Growth Arrest upon Cessation of TCR Signaling In Vivo

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