Diverse continuum of CD4+ T-cell states is determined by hierarchical additive integration of cytokine signals
Diverse continuum of CD4+ T-cell states is determined by hierarchical additive integration of cytokine signals
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DOI：
10.1073/pnas.1615590114
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发表时间：
2017-08-01
影响因子：
11.1
通讯作者：
Friedman, Nir
中科院分区：
文献类型：
--
作者：
Eizenberg-Magar, Inbal;Rimer, Jacob;Friedman, Nir
在细胞分化过程中，祖细胞整合来自其环境的信号，这些信号指导其发育成特化的表型。细胞对复杂信号组合的反应方式仍然难以分析和建模。为了进一步了解信号整合，我们系统地绘制了CD 4（+）T细胞对大量驱动其分化的输入细胞因子组合的反应。我们发现，在响应不同的输入组合，细胞分化成一个连续的细胞命运，而不是有限数量的离散表型。输入细胞因子分级地影响细胞群体，其中TGF β最占优势，其次是IL-6和IL-4。数学建模使用输入细胞因子组合的分层组内的加性信号整合来解释这些结果，并正确预测细胞群体对新输入条件的响应。这些发现表明，复杂的细胞反应可以使用分段线性方法有效地描述，为预测对新细胞因子组合和剂量的细胞反应提供了框架，并对微调免疫疗法产生影响。
During cell differentiation, progenitor cells integrate signals from their environment that guide their development into specialized phenotypes. The ways by which cells respond to complex signal combinations remain difficult to analyze and model. To gain additional insight into signal integration, we systematically mapped the response of CD4(+) T cells to a large number of input cytokine combinations that drive their differentiation. We find that, in response to varied input combinations, cells differentiate into a continuum of cell fates as opposed to a limited number of discrete phenotypes. Input cytokines hierarchically influence the cell population, with TGF beta being most dominant followed by IL-6 and IL-4. Mathematical modeling explains these results using additive signal integration within hierarchical groups of input cytokine combinations and correctly predicts cell population response to new input conditions. These findings suggest that complex cellular responses can be effectively described using a segmented linear approach, providing a framework for prediction of cellular responses to new cytokine combinations and doses, with implications to fine-tuned immunotherapies.