Title: Failed CTL/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time
Authors: Jenkins, MR
Rudd-Schmidt, JA
Lopez, JA
Ramsbottom, KM
Mannering, SI
Andrews, DM
Voskoboinik, I
Trapani, JA
Issue Year: 2015
Publisher ROCKEFELLER UNIV PRESS
Series JOURNAL OF EXPERIMENTAL MEDICINE: 212(3): 307-317
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-gamma (IFN-gamma) 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-gamma, and various chemokines is linked to failed disengagement of Prf-or Gzm-deficient lymphocytes from their targets, with mean synapse time increased fivefold, from similar to 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.
URI: https://publications.svi.edu.au/publications/1832
Other Identifiers 10.1084/jem.20140964
Publication type Article
Grant ID GNT1061961
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