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This article is part of the supplement: Kitasato Symposium 2011: Translational prospects for cytokines in 2011

Open Badges Oral presentation

Cytokine imprinting - mechanisms for memory

Andreas Radbruch

  • Correspondence: Andreas Radbruch

Author Affiliations

Deutsches Rheuma-Forschungszentrum Berlin, ein Leibniz Institut, Charitéplatz 1, 10117 Berlin, Germany

Arthritis Research & Therapy 2011, 13(Suppl 2):O12  doi:10.1186/ar3416

The electronic version of this article is the complete one and can be found online at:

Published:16 September 2011

© 2011 Radbruch.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Oral presentation

Imprinting of T helper lymphocytes for the reexpression of cytokines is crucial for protection against recurring pathogens but also can be a driving force of chronic inflammation. Th1 and Th17 cells are distinct lineages of proinflammatory effector/memory cells, imprinted for reexpression of interferon-γ (IFN-γ) and interleukin-17 (IL-17), by upregulated expression of the transcription factors T-bet and RORγt, respectively. Imprinting here means that while expression of the cytokine genes upon primary instruction requires signals from both, the T cell receptor and receptors for instructing cytokines, reexpression requires only T cell receptor signaling in reactivated effector/memory T cells. Interleukin-12 (IL-12) and IFN-γ are essential instruction signals for the differentiation of Th1 cells and the imprinting of the Ifng gene. In activated naïve T cells, IFN-γ induces the central Th1 transcription factor T-bet, while T-bet induces the expression of IFN-γ, in a positive, T cell receptor dependent feedback loop polarizing the T cell into Th1 differentiation. At this time, expression of the IL-12 receptor β2 chain (IL12Rβ2) is repressed by T cell receptor signaling. After TCR signaling has ceased, i.e. the antigen is eliminated, the IL12Rβ2 chain is expressed and IL-12 triggers a second wave of T-bet expression. This "late" T-bet expression coincides with expression of the transcription factors Hlx and Runx3, and it is required for imprinting of Th1 cells for the reexpression of IFN-γ. The signals required for Th17 differentiation and imprinting are less clearly defined. While signals such as TGF-β and IL-6 lead to the differentiation of IL-17 expressing cell in vitro, such cells fail to reexpress IL-17 in the absence of these instructive signals. In contrast, in vivo generated Th17 cells, have a stable memory for reexpression of IL-17 in vitro, upon restimulation by antigen. Such cells are refractory to Th1 or Th2 polarizing signals. Th cells coexpressing IFN-γ and IL-17 have been observed in vivo. Ex vivo isolated Th17 cells can be converted into Th1+17 cells by combined IFN-γ and IL-12 signaling. IFN-γ is required to upregulate expression of the IL12Rβ2 chain, and IL-12 for Th1 differentiation. These Th1+17 cells stably coexpress RORγt and T-bet on the single cell level, and are imprinted for reexpression of both IFN-γ and IL-17. Thus, for T lymphocytes, polarization and imprinting of inflammatory responses is regulated by dynamic interaction of IFN-γ and IL-12, and regulation of expression of the IL-12 receptor.