CARD8 inflammasome activation triggers pyroptosis in human T cells

Inflammasomes execute a unique type of cell death known as pyroptosis. Mostly characterized in myeloid cells, caspase-1 activation downstream of an inflammasome sensor results in the cleavage 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 blockingDPPs using Val-boroPro triggers a lytic form of cell death in primary humanCD4 andCD8 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 theCARD8-caspase-1-GSDMDaxis. Moreover,DPP9 constitutes the relevantDPPrestrainingCARD8 activation. Interestingly, thisCARD8-induced pyroptosis pathway can only be engaged in resting, but not in activated T cells. Altogether, these results broaden the relevance of inflammasome signaling and associated pyroptotic cell death to T cells, central players of the adaptive immune system.