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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.

Original publication

DOI

10.1016/j.immuni.2014.12.018

Type

Journal

Immunity

Publication Date

20/01/2015

Volume

42

Pages

108 - 122

Keywords

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