title: Individual T helper cells have a quantitative cytokine memory.
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.
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Helmstetter
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Flossdorf
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Peine
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany; Queensland Tropical Health Alliance Research Laboratory, James Cook University, Cairns Campus, Smithfield, QLD 4878, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kupz
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: 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; Department of Gastroenterology, Hepatology and Endocrinology, Charité, 10117 Berlin, Germany.
authors.forename: Ahmed N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Duque-Correa
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Yevhen
authors.initials: Y
authors.lastname: Vainshtein
authors.affiliation: German Rheumatism Research Center (DRFZ), a Leibniz Institute, 10117 Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Kaufmann
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Paul
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Bioquant Center, University of Heidelberg, 69120 Heidelberg, Germany. Electronic address: t.hoefer@dkfz-heidelberg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: 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. Electronic address: loehning@drfz.de.
authors.forename: Max
authors.initials: M
authors.lastname: Löhning
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D015169:Colony Count, Microbial; D005786:Gene Expression Regulation; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008962:Models, Theoretical; D017471:Receptors, Interferon / Q000235:genetics; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D059010:Single-Cell Analysis; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000821:virology; D019562:Viral Load; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D020825:T-Box Domain Proteins; D000096743:Interferon gamma Receptor; D000098815:T-bet Transcription Factor