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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.

Type

Journal article

Journal

Immunity

Publication Date

01/2015

Volume

42

Pages

108 - 122

Addresses

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.

Keywords

Th1 Cells, Cells, Cultured, Macrophages, Animals, Mice, Inbred C57BL, Mice, Transgenic, Mice, Knockout, Mice, Salmonella typhimurium, Lymphocytic choriomeningitis virus, Salmonella Infections, Lymphocytic Choriomeningitis, T-Box Domain Proteins, Receptors, Interferon, Colony Count, Microbial, Viral Load, Lymphocyte Activation, Cell Differentiation, Immunologic Memory, Gene Expression Regulation, Cell Lineage, Models, Theoretical, Interferon-gamma, Single-Cell Analysis