Individual T helper cells have a quantitative cytokine memory

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.

Item ID: 37297
Item Type: Article (Research - C1)
ISSN: 1097-4180
Funders: German Federal Ministry of Education and Research (BMBF), German Research Foundation (DFG), Volkswagen Foundation
Projects and Grants: BMBF FORSYS, BMBF e:Bio/T-Sys, DFG SFB618, DFG TPC3, DFG SFB65, DFG TP28, DFG LO1542/3-1, DFG HO02050/4-1
Date Deposited: 05 Mar 2015 04:07
FoR Codes: 06 BIOLOGICAL SCIENCES > 0605 Microbiology > 060502 Infectious Agents @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1103 Clinical Sciences > 110309 Infectious Diseases @ 40%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 20%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 65%
92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920109 Infectious Diseases @ 35%
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