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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02702

Long-term exposure to inflammation induces differential cytokine patterns and apoptosis in dendritic cells

  • 1Department of Oncology, Herlev Hospital, Denmark
  • 2Department of Biotechnology and Biomedicine, Technical University of Denmark, Denmark
  • 3Independent researcher, Denmark
  • 4National Center for Cancer Immune Therapy, CCIT-DK Department of Oncology, Herlev Hospital, Denmark

The activation of dendritic cells (DCs) has profound implications and governs the control of adaptive immunity. However, long-term activation might drive exhaustion of immune cells and negatively affect functionality. Here, long-term versus short-term exposure to bacterial lipopolysaccharide and interferon (IFN)γ was evaluated on human monocyte-derived DCs. Long-term activated DC1s began to undergo apoptosis concomitant with a profound TAM-receptor and efferocytosis-dependent induction of interleukin (IL)-10. Whereas levels of IL-12p70 and IL-10 were positively correlated upon short-term activation, an inverse association occured upon long-term activation and, while short-term activated CD1a+ DCs were main producers of IL-12p70, CD1a- DCs were the main fraction that underwent apoptosis and released IL-10 upon long-term activation. Moreover, pre-apoptotic long-term activated DCs were no longer able to activate alloreactive IFNγ-responsive T cells present in peripheral blood mononuclear cells from healthy volunteers. The IFNγ response was mediated by IL-12p70, as a strong reduction in IFNγ was observed following blockade with an IL-12p70 neutralizing antibody. Finally, multiplex analysis of DC supernatants revealed a particular pattern of proteins associated with apoptosis, cancer and chronic inflammation partly overlapping with gold standard DCs well-known for their inability to secrete IL-12p70. In conclusion, long-term activated DC1s significantly changed their profile towards a non-functional, tumour-promoting and anti-inflammatory phenotype.

Keywords: Dendritic Cells, Inflammation, Apoptosis, IL-12p70, IL-10

Received: 24 Jul 2019; Accepted: 04 Nov 2019.

Copyright: © 2019 Carstensen, Lie-Andersen, Obers, Crowther, Svane and Hansen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Morten Hansen, Department of Oncology, Herlev Hospital, Herlev, Denmark, morten.hansen.01@regionh.dk