Individual T helper cells have a quantitative cytokine memory.
Individual T helper cells have a quantitative cytokine memory.
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DOI：
10.1016/j.immuni.2014.12.018
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发表时间：
2015-01-20
期刊：
影响因子：
32.4
通讯作者：
Löhning M
中科院分区：
文献类型：
--
作者：
Helmstetter C;Flossdorf M;Peine M;Kupz A;Zhu J;Hegazy AN;Duque-Correa MA;Zhang Q;Vainshtein Y;Radbruch A;Kaufmann SH;Paul WE;Höfer T;Löhning M
细胞因子基因在分化的辅助性T （Th）细胞群中的概率表达仍然不明确。通过单细胞分析和数学建模，我们发现一种刺激具有稳定的细胞因子非产生因子和稳定的细胞因子产生因子，其表达量在细胞间具有广泛的可变性。关注干扰素-γ (IFN-γ)在Th1细胞中的表达，数学模型预测这种行为反映了不同的细胞内在能力，而不仅仅是基因表达噪音。在体内，被分泌的IFN-γ量纯化的Th1细胞对IFN-γ重新表达的概率和大小保持了至少1个月的定量记忆。从机制上讲，这种记忆源于单个等位基因的定量不同转录，并受Th1细胞系特异性转录因子T-bet的稳定表达差异控制。功能上，具有分级IFN-γ生产能力的Th1细胞不同程度地激活沙门氏菌感染的巨噬细胞以杀死细菌。因此，单个Th细胞承诺产生不同数量的给定细胞因子，从而产生功能性群体内异质性。
The probabilistic expression of cytokine genes in differentiated T helper (Th) cell populations remains ill defined. By single-cell analyses and mathematical modeling, we show that one stimulation featured stable cytokine nonproducers as well as stable producers with wide cell-to-cell variability in the magnitude of expression. Focusing on interferon-γ (IFN-γ) expression by Th1 cells, mathematical modeling predicted that this behavior reflected different cell-intrinsic capacities and not mere gene-expression noise. In vivo, Th1 cells sort purified by secreted IFN-γ amounts preserved a quantitative memory for both probability and magnitude of IFN-γ re-expression for at least 1 month. Mechanistically, this memory resulted from quantitatively distinct transcription of individual alleles and was controlled by stable expression differences of the Th1 cell lineage-specifying transcription factor T-bet. Functionally, Th1 cells with graded IFN-γ production competence differentially activated Salmonella-infected macrophages for bacterial killing. Thus, individual Th cells commit to produce distinct amounts of a given cytokine, thereby generating functional intrapopulation heterogeneity.