Helmstetter Caroline, Flossdorf Michael, Peine Michael, Kupz Andreas, Zhu Jinfang, Hegazy Ahmed N, Duque-Correa Maria A, Zhang Qin, Vainshtein Yevhen, Radbruch Andreas, Kaufmann Stefan H, Paul William E, Höfer Thomas, Löhning Max
Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, 10117 Berlin, Germany; German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany.
Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
Immunity. 2015 Jan 20;42(1):108-22. doi: 10.1016/j.immuni.2014.12.018. Epub 2014 Dec 25.
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.
分化的辅助性T（Th）细胞群体中细胞因子基因的概率表达仍不清楚。通过单细胞分析和数学建模，我们发现一种刺激方式既有稳定的细胞因子不产生者，也有稳定的产生者，其表达量在细胞间存在很大差异。以Th1细胞产生的干扰素-γ（IFN-γ）为例，数学建模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声。在体内，通过分泌的IFN-γ量纯化的Th1细胞至少在1个月内保留了IFN-γ重新表达的概率和量的定量记忆。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细胞谱系特异性转录因子T-bet的稳定表达差异控制。在功能上，具有不同IFN-γ产生能力的Th1细胞对感染沙门氏菌的巨噬细胞进行不同程度的激活以杀灭细菌。因此，单个Th细胞产生特定细胞因子的量不同，从而在群体内产生功能异质性。
