Quantitative and Qualitative Signals Determine T-Cell Cycle Entry and Progression

Modiano, Jaime F.; Mayor, Jocelyne; Ball, Carrie R.; Chitko-McKown, Carol G.; Sakata, Naoaki; Domenico-Hahn, Joanne; Lucas, Joseph J.; Gelfand, Erwin W.

doi:10.1006/cimm.1999.1563

Cited by 25 publications

(23 citation statements)

References 45 publications

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“…A shorter activation delay time is, however, likely to play a role in determining the rapidity of recall responses by memory cells. Several groups have reported that the time delay between activation and the first mitotic event is shorter for memory than naive T cells (32,48,49). Indeed, memory T cells require 10-fold shorter exposure to Ag (1 h vs 10 -20 h for naive T cells) for commitment to maximal proliferation (31), likely due to preassembly of the CD3 ϩ TCR complex in memory cells (29).…”

Section: Discussionmentioning

confidence: 99%

“…IL-2 increases the proportion of activated T cells progressing from G 0 to S phase, as does CD28 ligation (32)(33)(34). Although these factors are important for determining the magnitude of the responding CD4 ϩ T cell mass, our model has simplified this event to a single activation probability distribution reflecting this heterogeneity.…”

Section: Activation Delay Periodmentioning

confidence: 99%

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Discrete Event Modeling of CD4+ Memory T Cell Generation

Zand

Briggs

Bose

et al. 2004

The Journal of Immunology

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Studies of memory T cell differentiation are hampered by a lack of quantitative models to test hypotheses in silico before in vivo experimentation. We created a stochastic computer model of CD4+ memory T cell generation that can simulate and track 101–108 individual lymphocytes over time. Parameters for the model were derived from experimental data using naive human CD4+ T cells stimulated in vitro. Using discrete event computer simulation, we identified two key variables that heavily influence effector burst size and the persistent memory pool size: the cell cycle dependent probability of apoptosis, and the postactivation mitosis at which memory T cells emerge. Multiple simulations were performed and varying critical parameters permitted estimates of how sensitive the model was to changes in all of the model parameters. We then compared two hypotheses of CD4+ memory T cell generation: maturation from activated naive to effector to memory cells (model I) vs direct progression from activated naive to memory cells (model II). We find that direct progression of naive to memory T cells does not explain published measurements of the memory cell mass unless postactivation expansion of the memory cell cohort occurs. We conclude that current models suggesting direct progression of activated naive cells to the persistent memory phenotype (model II) do not account for the experimentally measured size of the postactivation CD4+, Ag-specific, memory T cell cohort.

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Section: Discussionmentioning

confidence: 99%

Section: Activation Delay Periodmentioning

confidence: 99%

Discrete Event Modeling of CD4+ Memory T Cell Generation

Zand

Briggs

Bose

et al. 2004

The Journal of Immunology

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“…T cells were stimulated to acquire competence (traverse the G 0 /G 1 transition and respond to IL-2 progression signals) using soluble anti-CD3 (10 ng/ml) or a submitogenic dose of PHA (0.5 g/ml) for 30 min followed by rigorous washing (Modiano et al, 1999). To ensure reproducibility of the data, proliferative responses were measured independently in two laboratories (T.C.…”

Section: Methodsmentioning

confidence: 99%

“…To address this paradox, we chose to examine the effects of nicotine on cell cycle entry and progression using a "competence and progression" system of human peripheral blood T lymphocytes (PBTs) (Modiano et al, 1999). We chose this system because, unlike other cultured cells, PBTs comprise a population of normal cells in G 0 that can be synchronously stimulated to enter the cell cycle, thus providing a fairly unique opportunity to gain insights into the effects of nicotine not only on G 1 phase progression but also on the transition from G 0 to G 1 .…”

mentioning

confidence: 99%

Nicotine Activates Nuclear Factor of Activated T Cells c2 (NFATc2) and Prevents Cell Cycle Entry in T Cells

Frazer‐Abel¹,

Baksh²,

Fosmire³

et al. 2004

J Pharmacol Exp Ther

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We used primary peripheral blood T cells, a population that exists in G 0 and can be stimulated to enter the cell cycle synchronously, to define more precisely the effects of nicotine on pathways that control cell cycle entry and progression. Our data show that nicotine decreased the ability of T cells to transit through the G 0 /G 1 boundary (acquire competence) and respond to progression signals. These effects were due to nuclear factor of activated T cells c2 (NFATc2)-dependent repression of cyclin-dependent kinase 4 (CDK4) expression. Growth arrest at the G 0 /G 1 boundary was further enforced by inhibition of cyclin D2 expression and by increased expression and stabilization of p27Kip1. Intriguingly, T cells from habitual users of tobacco products and from NFATc2-deficient mice constitutively expressed CDK4 and were resistant to the antiproliferative effects of nicotine. These results indicate that nicotine impairs T cell cycle entry through NFATc2-dependent mechanisms and suggest that, in the face of chronic nicotine exposure, selection may favor cells that can evade these effects. We postulate that cross talk between nicotinic acetylcholine receptors and growth factor receptor-activated pathways offers a novel mechanism by which nicotine may directly impinge on cell cycle progression. This offers insight into possible reasons that underlie the unique effects of nicotine on distinct cell types and identifies new targets that may be useful control tobacco-related diseases.Previous studies show that nicotine can act as a mitogen in endothelial and smooth muscle cells (Carty et al., 1997;Villablanca, 1998), but it can inhibit proliferation of lymphocytes and other cells (Theilig et al

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“…Human peripheral blood T cells were rendered competent to proliferate (cytokine-responsive) by stimulation with a submitogenic concentration of PHA (0.5 g/ml) for 1 h followed by extensive washing (13). For each submitogenic stimulation experiment, an equal number of T cells was allowed to remain unstimulated, or was stimulated to proliferate by a mitogenic concentration of 10 g/ml PHA.…”

Section: Induction Of Competencementioning

confidence: 99%

CDK4 Expression and Activity Are Required for Cytokine Responsiveness in T Cells

Modiano

Mayor

Ball

et al. 2000

The Journal of Immunology

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Stimulation of lymphocytes through the Ag receptor can lead to cytokine responsiveness or unresponsiveness. We examined the importance of cyclin-dependent kinase (CDK)4 to establish and maintain IL-2 responsiveness in human T cells. Our results show that a herbimycin A- and staurosporine-sensitive phase of CDK4 expression and activity preceded the acquisition of IL-2-responsiveness in mitogen-stimulated peripheral blood T cells. Intriguingly, CDK4 expression and activity were demonstrable in purified unstimulated peripheral blood T cells from ∼30% (5/16) of healthy individuals examined for this study. These T cells proliferated in response to IL-2 without additional mitogens, and both the expression and activity of CDK4 and the ability to respond to cytokines were resistant to herbimycin A and staurosporine. The pattern of CDK4 expression and response to IL-2 in this subset of individuals resembled that seen in the human IL-2-dependent Kit-225 T cell line. However, in contrast to normal T cells, Kit-225 cells were rendered unresponsive to IL-2 by stimulation through the Ag receptor. In these cells, PHA, anti-CD3, or PMA induced marked reductions of CDK4 expression and activity that paralleled IL-2 unresponsiveness, and these effects were not reversible by IL-2. Furthermore, IL-2-dependent proliferation could be similarly inhibited in Kit-225 cells by overexpression of the CDK inhibitors p16/Ink4-a or p21/Waf-1a or by overexpression of a kinase-inactive CDK4 mutant. The data indicate that CDK4 expression and activity are necessary to induce and maintain cytokine responsiveness in T cells, suggesting that CDK4 is important to link T cell signaling pathways to the machinery that controls cell cycle progression.

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Quantitative and Qualitative Signals Determine T-Cell Cycle Entry and Progression

Cited by 25 publications

References 45 publications

Discrete Event Modeling of CD4+ Memory T Cell Generation

Discrete Event Modeling of CD4+ Memory T Cell Generation

Nicotine Activates Nuclear Factor of Activated T Cells c2 (NFATc2) and Prevents Cell Cycle Entry in T Cells

CDK4 Expression and Activity Are Required for Cytokine Responsiveness in T Cells

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