Stochastic model of T cell proliferation: A calculus revealing IL-2 regulation of precursor frequencies, cell cycle time, and survival
Stochastic model of T cell proliferation: A calculus revealing IL-2 regulation of precursor frequencies, cell cycle time, and survival
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DOI：
10.4049/jimmunol.170.10.4963
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发表时间：
2003-05-15
影响因子：
4.4
通讯作者：
Hodgkin, PD
中科院分区：
文献类型：
--
作者：
Deenick, EK;Gett, AV;Hodgkin, PD
Ag暴露的结果由T细胞增殖的复杂调节决定。增殖和存活的速率被细胞接收并整合以实现净响应的许多信号改变。我们之前已经说明了即使在IL-2饱和的条件下，动力学参数的微小变化如何导致大的差异。在这项研究中，我们研究了不同的IL-2浓度对T细胞反应的影响，并建立了一个模型，将额外的增殖和生存参数。引人注目的是，进入第一次分裂的细胞比例，而不是它们进入的时间，被IL-2显着改变。此外，IL-2浓度也会改变后期分裂中细胞的存活率和平均分裂时间。总之，对这些参数的小的同时影响导致总细胞数的大的差异。这些结果揭示了如何在体外系统可能夸大IL-2的贡献，从而如何共刺激或额外的辅助细胞，改变IL-2浓度，即使是相对较小的量，将产生大的体外细胞数量的差异，因此出现强制性。此外，它们说明了T细胞活化的定量模型如何阐明T细胞如何在原位处理复杂的信号整合，因此更恰当地帮助发展行为理论。
The outcome of Ag exposure is dictated by complex regulation of T cell proliferation. The rates of proliferation and survival are altered by numerous signals that the cell receives and integrates to achieve a net response. We have illustrated previously how small changes in kinetic parameters can lead to large differences, even under conditions of saturating IL-2. In this study, we examine the effect of varying IL-2 concentration on T cell response and develop a model incorporating additional parameters of proliferation and survival. Strikingly, the proportion of cells that enter the first division, but not the time at which they enter, is dramatically altered by IL-2. Furthermore, the survival and average division time of cells in later divisions are also altered by IL-2 concentration. Together, the small simultaneous effects on these parameters result in large differences in total cell number. These results reveal how in vitro systems may exaggerate the contribution of IL-2, and thus how costimuli or additional helper cells that alter IL-2 concentration, even by relatively small amounts, will generate large in vitro differences in cell number and therefore appear obligatory. Furthermore, they illustrate how a quantitative model of T cell activation can clarify how complex signal integration is handled by T cells in situ, and therefore more appropriately aid development of a theory of behavior.