A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells
A Mathematical Model for the Reciprocal Differentiation of T Helper 17 Cells and Induced Regulatory T Cells
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DOI：
10.1371/journal.pcbi.1002122
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发表时间：
2011-07-01
影响因子：
4.3
通讯作者：
Tyson, John J.
中科院分区：
文献类型：
--
作者：
Hong, Tian;Xing, Jianhua;Tyson, John J.
T辅助细胞17（T（H）17）和诱导的调节性T（iT（reg））细胞的相互分化在多种人类炎症性疾病的发病机制和解决中起着关键作用。虽然最初的研究表明T（H）17或iT（reg）谱系的稳定承诺，但最近的结果显示了显着的可塑性和异质性，这反映在分化的效应细胞在T（H）17和iT（reg）谱系中重编程的能力以及一组幼稚前体CD 4（+）T细胞可以通过相同的分化信号转化生长因子β编程为表型多样的群体。为了调和这些观察结果，我们建立了一个数学模型的T（H）17/iT（reg）分化，表现出四个不同的稳定的稳态，由干草叉分叉与一定程度的对称性破缺。根据该模型，一组具有一些小的细胞间变异性的前体细胞可以分化成表型不同的细胞亚群，这些细胞亚群表现出两种T细胞谱系的主转录因子调节因子的不同水平。具有这些特性的动态控制系统足够灵活，可以通过极化信号（如白细胞介素-6和视黄酸）沿替代途径转向，并且免疫系统可以使用它来响应一系列分化信号以所需的分数产生功能不同的效应细胞。此外，该模型提出了一个定量的解释与两个主调节器的高表达水平的表型。这种表型对应于再稳定的共表达状态，出现在分化的晚期，而不是在一些其他情况下观察到的双能前体状态。我们的模拟调和了大多数已发表的实验观察结果，并预测了新的分化状态以及尚未在实验中观察到的不同表型之间的转换。
The reciprocal differentiation of T helper 17 (T(H)17) cells and induced regulatory T (iT(reg)) cells plays a critical role in both the pathogenesis and resolution of diverse human inflammatory diseases. Although initial studies suggested a stable commitment to either the T(H)17 or the iT(reg) lineage, recent results reveal remarkable plasticity and heterogeneity, reflected in the capacity of differentiated effectors cells to be reprogrammed among T(H)17 and iT(reg) lineages and the intriguing phenomenon that a group of naive precursor CD4(+) T cells can be programmed into phenotypically diverse populations by the same differentiation signal, transforming growth factor beta. To reconcile these observations, we have built a mathematical model of T(H)17/iT(reg) differentiation that exhibits four different stable steady states, governed by pitchfork bifurcations with certain degrees of broken symmetry. According to the model, a group of precursor cells with some small cell-to-cell variability can differentiate into phenotypically distinct subsets of cells, which exhibit distinct levels of the master transcription-factor regulators for the two T cell lineages. A dynamical control system with these properties is flexible enough to be steered down alternative pathways by polarizing signals, such as interleukin-6 and retinoic acid and it may be used by the immune system to generate functionally distinct effector cells in desired fractions in response to a range of differentiation signals. Additionally, the model suggests a quantitative explanation for the phenotype with high expression levels of both master regulators. This phenotype corresponds to a re-stabilized co-expressing state, appearing at a late stage of differentiation, rather than a bipotent precursor state observed under some other circumstances. Our simulations reconcile most published experimental observations and predict novel differentiation states as well as transitions among different phenotypes that have not yet been observed experimentally.