Individual T helper cells have a quantitative cytokine memory
2015
Authors: Helmstetter C, Flossdorf M, Peine M, Kupz A, Zhu J, Hegazy AN, Duque-Correa MA, Zhang Q, Vainshtein Y, Radbruch A, Kaufmann SH, Paul WE, Höfer T, Löhning M
CellNetworks People: Höfer Thomas
Journal: Immunity. 2015 Jan 20;42(1):108-22. doi: 10.1016/j.immuni.2014.12.018

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.