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Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time

Failure of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to kill target cells by perforin (Prf)/granzyme (Gzm)-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, Prf-deficient infants suffer a fatal “cytokine storm” resulting from macr...

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Autores principales: Jenkins, Misty R., Rudd-Schmidt, Jesse A., Lopez, Jamie A., Ramsbottom, Kelly M., Mannering, Stuart I., Andrews, Daniel M., Voskoboinik, Ilia, Trapani, Joseph A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354371/
https://www.ncbi.nlm.nih.gov/pubmed/25732304
http://dx.doi.org/10.1084/jem.20140964
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author Jenkins, Misty R.
Rudd-Schmidt, Jesse A.
Lopez, Jamie A.
Ramsbottom, Kelly M.
Mannering, Stuart I.
Andrews, Daniel M.
Voskoboinik, Ilia
Trapani, Joseph A.
author_facet Jenkins, Misty R.
Rudd-Schmidt, Jesse A.
Lopez, Jamie A.
Ramsbottom, Kelly M.
Mannering, Stuart I.
Andrews, Daniel M.
Voskoboinik, Ilia
Trapani, Joseph A.
author_sort Jenkins, Misty R.
collection PubMed
description Failure of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to kill target cells by perforin (Prf)/granzyme (Gzm)-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, Prf-deficient infants suffer a fatal “cytokine storm” resulting from macrophage overactivation, but the link to failed target cell death is not understood. We show that prolonged target cell survival greatly amplifies the quanta of inflammatory cytokines secreted by CTLs/NK cells and that interferon-γ (IFN-γ) directly invokes the activation and secondary overproduction of proinflammatory IL-6 from naive macrophages. Furthermore, using live cell microscopy to visualize hundreds of synapses formed between wild-type, Prf-null, or GzmA/B-null CTLs/NK cells and their targets in real time, we show that hypersecretion of IL-2, TNF, IFN-γ, and various chemokines is linked to failed disengagement of Prf- or Gzm-deficient lymphocytes from their targets, with mean synapse time increased fivefold, from ∼8 to >40 min. Surprisingly, the signal for detachment arose from the dying target cell and was caspase dependent, as delaying target cell death with various forms of caspase blockade also prevented their disengagement from fully competent CTLs/NK cells and caused cytokine hypersecretion. Our findings provide the cellular mechanism through which failed killing by lymphocytes causes systemic inflammation involving recruitment and activation of myeloid cells.
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spelling pubmed-43543712015-09-09 Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time Jenkins, Misty R. Rudd-Schmidt, Jesse A. Lopez, Jamie A. Ramsbottom, Kelly M. Mannering, Stuart I. Andrews, Daniel M. Voskoboinik, Ilia Trapani, Joseph A. J Exp Med Brief Definitive Report Failure of cytotoxic T lymphocytes (CTLs) or natural killer (NK) cells to kill target cells by perforin (Prf)/granzyme (Gzm)-induced apoptosis causes severe immune dysregulation. In familial hemophagocytic lymphohistiocytosis, Prf-deficient infants suffer a fatal “cytokine storm” resulting from macrophage overactivation, but the link to failed target cell death is not understood. We show that prolonged target cell survival greatly amplifies the quanta of inflammatory cytokines secreted by CTLs/NK cells and that interferon-γ (IFN-γ) directly invokes the activation and secondary overproduction of proinflammatory IL-6 from naive macrophages. Furthermore, using live cell microscopy to visualize hundreds of synapses formed between wild-type, Prf-null, or GzmA/B-null CTLs/NK cells and their targets in real time, we show that hypersecretion of IL-2, TNF, IFN-γ, and various chemokines is linked to failed disengagement of Prf- or Gzm-deficient lymphocytes from their targets, with mean synapse time increased fivefold, from ∼8 to >40 min. Surprisingly, the signal for detachment arose from the dying target cell and was caspase dependent, as delaying target cell death with various forms of caspase blockade also prevented their disengagement from fully competent CTLs/NK cells and caused cytokine hypersecretion. Our findings provide the cellular mechanism through which failed killing by lymphocytes causes systemic inflammation involving recruitment and activation of myeloid cells. The Rockefeller University Press 2015-03-09 /pmc/articles/PMC4354371/ /pubmed/25732304 http://dx.doi.org/10.1084/jem.20140964 Text en © 2015 Jenkins et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Brief Definitive Report
Jenkins, Misty R.
Rudd-Schmidt, Jesse A.
Lopez, Jamie A.
Ramsbottom, Kelly M.
Mannering, Stuart I.
Andrews, Daniel M.
Voskoboinik, Ilia
Trapani, Joseph A.
Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
title Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
title_full Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
title_fullStr Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
title_full_unstemmed Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
title_short Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
title_sort failed ctl/nk cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
topic Brief Definitive Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354371/
https://www.ncbi.nlm.nih.gov/pubmed/25732304
http://dx.doi.org/10.1084/jem.20140964
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