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, CARD 8 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 DPP s using Val‐boroPro triggers a lytic form of cell death in primary human CD 4 and CD 8 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 CARD 8‐caspase‐1‐ GSDMD axis. Moreover, DPP 9 constitutes the relevant DPP restraining CARD 8 activation. Interestingly, this CARD 8‐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.