Journal article
Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
MR Jenkins, JA Rudd-Schmidt, JA Lopez, KM Ramsbottom, SI Mannering, DM Andrews, I Voskoboinik, JA Trapani
Journal of Experimental Medicine | Published : 2015
DOI: 10.1084/jem.20140964
Abstract
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 ..
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Funding Acknowledgements
M.R. Jenkins is supported by a National Health and Medical Research Council of Australia (NHMRC)/R.G. Menzies postdoctoral training fellowship and an NHMRC New Investigator Project Grant. J.A. Lopez is supported by an NHMRC postdoctoral training fellowship. D.M. Andrews is supported by an NHMRC Career Development Fellowship. I. Voskoboinik and J.A. Trapani are supported by fellowships and project and program grants from the NHMRC. S.I. Mannering is supported by the NHMRC, JDRF, and Diabetes Australia Research Trust (DART).