gms | German Medical Science

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018)

23.10. - 26.10.2018, Berlin

IL-15 antagonizes trauma induced suppression of NK cells – potential involvement of c-Kit

Meeting Abstract

  • presenting/speaker Björn Bösken - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Monika Hepner-Schefczyk - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Lea Boller - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Sonja Vonderhagen - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Ivo Michiels - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Marcel Dudda - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Marcus Jäger - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany
  • Stefanie Flohé - Universitätsklinikum Essen, Klinik für Orthopädie und Unfallchirurgie, Essen, Germany

Deutscher Kongress für Orthopädie und Unfallchirurgie (DKOU 2018). Berlin, 23.-26.10.2018. Düsseldorf: German Medical Science GMS Publishing House; 2018. DocGF19-95

doi: 10.3205/18dkou512, urn:nbn:de:0183-18dkou5121

Veröffentlicht: 6. November 2018

© 2018 Bösken et al.
Dieser Artikel ist ein Open-Access-Artikel und steht unter den Lizenzbedingungen der Creative Commons Attribution 4.0 License (Namensnennung). Lizenz-Angaben siehe http://creativecommons.org/licenses/by/4.0/.


Gliederung

Text

Objectives: Severe tissue damage induced by traumatic or surgical injury causes the development of immunosuppression that is associated with an enhanced susceptibility to nosocomial infections. Cluster of differentiation (CD) 56bright natural killer (NK) cells are a subset of NK cells with highly regulatory cytokine production.

Previous work of our group has shown that the capacity of these cells to produce Interferon (IFN) γ in the context of Staphylococcus aureus infection is suppressed in patients after trauma. This effect is partly caused by a downregulation of the β2 subunit of the interleukin 12 receptor (IL-12R) and reduced responsiveness to interleukin (IL) 12. The maximum of this effect occurs on day eight after trauma. We found comparable effects of the immune system in patients after multiple trauma and patients after invasive spine surgery with intense tissue damage.

Here, we investigated which factors are responsible for the downregulation of IL-12Rβ2 on CD56bright NK cells. Furthermore we attempt to identify strategies to restore the expression of IL-12Rβ2 and subsequently the production of IFN-γ.

Methods: We obtained blood samples of severely injured patients (ISS>16) and from patients undergoing major spine surgery before and one, five and eight days after the procedure (n=9). Peripheral blood mononuclear cells were isolated and the expression of diverse surface molecules and transcription factors was determined on gated CD56bright NK cells ex vivo. In addition, the cells were exposed to heat-killed S. aureus (HKSA), as a model for infection, in the presence or absence of IL-15 and the expression of IFN-γ and different surface molecules of CD56bright NK cells was analyzed by flow cytometry.

Results and conclusion: We found no difference in the expression of T-bet and Eomesodermin, two master regulators of IFN-γ transcription, between day one (d1) and day eight (d8) after trauma. On d8 the expression of CD94 on CD56bright NK cells was not decreased in comparison to d1, which would have indicated an immature developmental stage. The expression of c-Kit (CD117), also known as receptor for stem cell factor, increased from d1 to d8 after trauma predominantly on IL-12R β2- cells. Exposure of the patients' CD56bright NK cells on d8 after trauma to IL-15, a potent pro-inflammatory cytokine with critical function in NK cell development, decreased the expression of c-Kit while it increased the expression of IL-12Rβ2 and restored the production of IFN-γ.

Here, we show that the unresponsiveness of CD56bright NK cells 8d after severe injury is associated with an increased expression of c-Kit. IL-15 impairs the expression of c-Kit while it increases the expression of IL-12Rβ2 and restores the production of IFN- γ. Thus, IL-15 might represent a potential target for the therapy of immunosuppression after severe trauma. Furthermore c-Kit might act as a novel player in the origin of NK cell suppression after major injury.