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., Hofer, Thomas, and Lohning, Max (2015) Individual T helper cells have a quantitative cytokine memory. Immunity, 42 (1). pp. 108-122.

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Abstract

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.

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