Cargando…

An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury

Major trauma-induced tissue injury causes a dysregulation of the immune system. Severe systemic inflammation occurs early after the insult. Later on, an enhanced risk for life-threatening opportunistic infections develops that culminates at the end of the first week after trauma. CD56(bright) Natura...

Descripción completa

Detalles Bibliográficos
Autores principales: Bösken, Björn, Hepner-Schefczyk, Monika, Vonderhagen, Sonja, Dudda, Marcel, Flohé, Stefanie B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330140/
https://www.ncbi.nlm.nih.gov/pubmed/32670280
http://dx.doi.org/10.3389/fimmu.2020.01200
_version_ 1783553051399815168
author Bösken, Björn
Hepner-Schefczyk, Monika
Vonderhagen, Sonja
Dudda, Marcel
Flohé, Stefanie B.
author_facet Bösken, Björn
Hepner-Schefczyk, Monika
Vonderhagen, Sonja
Dudda, Marcel
Flohé, Stefanie B.
author_sort Bösken, Björn
collection PubMed
description Major trauma-induced tissue injury causes a dysregulation of the immune system. Severe systemic inflammation occurs early after the insult. Later on, an enhanced risk for life-threatening opportunistic infections develops that culminates at the end of the first week after trauma. CD56(bright) Natural killer (NK) cells play a key role in the defense against infection due to their rapid release of Interferon (IFN) γ in response to Interleukin (IL) 12. NK cells are impaired in IFN-γ synthesis after severe injury due to a disturbed IL-12/IFN-γ axis. Thereby, a circulating factor mediates extrinsic suppression of NK cells. Yet unknown cell-intrinsic mechanisms manifest by day 8 after trauma and render NK cells unresponsive to stimulatory cytokines. In the present study, we investigated the origin of such late NK cell-intrinsic suppression after major trauma. Peripheral blood mononuclear cells (PBMC) were isolated from patients 8 day after severe injury and from healthy control subjects and were stimulated with inactivated Staphylococcus aureus. The expression of diverse cytokine receptors, intracellular signaling molecules, and the secretion of IFN-γ by CD56(bright) NK cells were examined. After stimulation with S. aureus, NK cells from patients expressed enhanced levels of c-kit/CD117 that inversely correlated with IFN-γ synthesis and IL-12 receptor (IL-12R) β2 expression. Supplementation with IL-15 and inhibition of the transforming growth factor receptor (TGF-βR) I reduced CD117 expression and increased the level of IL-12Rβ2 and IFN-γ. NK cells from patients showed reduced phosphorylation of mammalian target of rapamycin (mTOR). Addition of IL-15 at least partly restored mTOR phosphorylation and increased IL-12Rβ2 expression. The reduced mTOR phosphorylation after severe injury was cell-intrinsic as it was not induced by serum factors. Inhibition of mTOR in purified NK cells from healthy donors by rapamycin decreased the synthesis of IFN-γ. Thus, impaired mTOR phosphorylation in response to a microbial challenge contributes to the cell-intrinsic mechanisms that underlie NK cell dysregulation after trauma. Restoration of the mTOR phosphorylation capacity along with inhibition of the TGF-βRI signaling in NK cells after severe injury might improve the immune defense against opportunistic infections.
format Online
Article
Text
id pubmed-7330140
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-73301402020-07-14 An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury Bösken, Björn Hepner-Schefczyk, Monika Vonderhagen, Sonja Dudda, Marcel Flohé, Stefanie B. Front Immunol Immunology Major trauma-induced tissue injury causes a dysregulation of the immune system. Severe systemic inflammation occurs early after the insult. Later on, an enhanced risk for life-threatening opportunistic infections develops that culminates at the end of the first week after trauma. CD56(bright) Natural killer (NK) cells play a key role in the defense against infection due to their rapid release of Interferon (IFN) γ in response to Interleukin (IL) 12. NK cells are impaired in IFN-γ synthesis after severe injury due to a disturbed IL-12/IFN-γ axis. Thereby, a circulating factor mediates extrinsic suppression of NK cells. Yet unknown cell-intrinsic mechanisms manifest by day 8 after trauma and render NK cells unresponsive to stimulatory cytokines. In the present study, we investigated the origin of such late NK cell-intrinsic suppression after major trauma. Peripheral blood mononuclear cells (PBMC) were isolated from patients 8 day after severe injury and from healthy control subjects and were stimulated with inactivated Staphylococcus aureus. The expression of diverse cytokine receptors, intracellular signaling molecules, and the secretion of IFN-γ by CD56(bright) NK cells were examined. After stimulation with S. aureus, NK cells from patients expressed enhanced levels of c-kit/CD117 that inversely correlated with IFN-γ synthesis and IL-12 receptor (IL-12R) β2 expression. Supplementation with IL-15 and inhibition of the transforming growth factor receptor (TGF-βR) I reduced CD117 expression and increased the level of IL-12Rβ2 and IFN-γ. NK cells from patients showed reduced phosphorylation of mammalian target of rapamycin (mTOR). Addition of IL-15 at least partly restored mTOR phosphorylation and increased IL-12Rβ2 expression. The reduced mTOR phosphorylation after severe injury was cell-intrinsic as it was not induced by serum factors. Inhibition of mTOR in purified NK cells from healthy donors by rapamycin decreased the synthesis of IFN-γ. Thus, impaired mTOR phosphorylation in response to a microbial challenge contributes to the cell-intrinsic mechanisms that underlie NK cell dysregulation after trauma. Restoration of the mTOR phosphorylation capacity along with inhibition of the TGF-βRI signaling in NK cells after severe injury might improve the immune defense against opportunistic infections. Frontiers Media S.A. 2020-06-25 /pmc/articles/PMC7330140/ /pubmed/32670280 http://dx.doi.org/10.3389/fimmu.2020.01200 Text en Copyright © 2020 Bösken, Hepner-Schefczyk, Vonderhagen, Dudda and Flohé. http://creativecommons.org/licenses/by/4.0/ 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.
spellingShingle Immunology
Bösken, Björn
Hepner-Schefczyk, Monika
Vonderhagen, Sonja
Dudda, Marcel
Flohé, Stefanie B.
An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury
title An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury
title_full An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury
title_fullStr An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury
title_full_unstemmed An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury
title_short An Inverse Relationship Between c-Kit/CD117 and mTOR Confers NK Cell Dysregulation Late After Severe Injury
title_sort inverse relationship between c-kit/cd117 and mtor confers nk cell dysregulation late after severe injury
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330140/
https://www.ncbi.nlm.nih.gov/pubmed/32670280
http://dx.doi.org/10.3389/fimmu.2020.01200
work_keys_str_mv AT boskenbjorn aninverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT hepnerschefczykmonika aninverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT vonderhagensonja aninverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT duddamarcel aninverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT flohestefanieb aninverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT boskenbjorn inverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT hepnerschefczykmonika inverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT vonderhagensonja inverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT duddamarcel inverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury
AT flohestefanieb inverserelationshipbetweenckitcd117andmtorconfersnkcelldysregulationlateaftersevereinjury