Inflammasomes execute a unique type of cell death known as pyroptosis. Mostly characterized in myeloid cells, caspase-1 activa- tion downstream of an inflammasome sensor results in the cleav- age and activation of gasdermin D (GSDMD), which then forms a lytic pore in the plasma membrane. Recently, CARD8 was identified as a novel inflammasome sensor that triggers pyroptosis in myeloid leukemia cells upon inhibition of dipeptidyl-peptidases (DPP). Here, we show that blocking DPPs using Val-boroPro triggers a lytic form of cell death in primary human CD4 and CD8 T cells, while other prototypical inflammasome stimuli were not active. This cell death displays morphological and biochemical hallmarks of pyroptosis. By genetically dissecting candidate components in primary T cells, we identify this response to be dependent on the CARD8-caspase-1- GSDMD axis. Moreover, DPP9 constitutes the relevant DPP restrain- ing CARD8 activation. Interestingly, this CARD8-induced pyroptosis pathway can only be engaged in resting, but not in activated T cells. Altogether, these results broaden the relevance of inflamma- some signaling and associated pyroptotic cell death to T cells, central players of the adaptive immune system.
CARD8 inflammasome activation triggers pyroptosis in human T cells / A. Linder, S. Bauernfried, Y. Cheng, M. Albanese, C. Jung, O. Keppler, V. Hornung. - In: EMBO JOURNAL. - ISSN 1460-2075. - 39:19(2020), pp. e105071.1-e105071.16. [10.15252/embj.2020105071]
CARD8 inflammasome activation triggers pyroptosis in human T cells
M. Albanese;
2020
Abstract
Inflammasomes execute a unique type of cell death known as pyroptosis. Mostly characterized in myeloid cells, caspase-1 activa- tion downstream of an inflammasome sensor results in the cleav- age and activation of gasdermin D (GSDMD), which then forms a lytic pore in the plasma membrane. Recently, CARD8 was identified as a novel inflammasome sensor that triggers pyroptosis in myeloid leukemia cells upon inhibition of dipeptidyl-peptidases (DPP). Here, we show that blocking DPPs using Val-boroPro triggers a lytic form of cell death in primary human CD4 and CD8 T cells, while other prototypical inflammasome stimuli were not active. This cell death displays morphological and biochemical hallmarks of pyroptosis. By genetically dissecting candidate components in primary T cells, we identify this response to be dependent on the CARD8-caspase-1- GSDMD axis. Moreover, DPP9 constitutes the relevant DPP restrain- ing CARD8 activation. Interestingly, this CARD8-induced pyroptosis pathway can only be engaged in resting, but not in activated T cells. Altogether, these results broaden the relevance of inflamma- some signaling and associated pyroptotic cell death to T cells, central players of the adaptive immune system.File | Dimensione | Formato | |
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