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 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 restraining 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 inflammasome signaling and associated pyroptotic cell death to T cells, central players of the adaptive immune system.

中文翻译：

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CARD8炎性小体激活触发人T细胞的焦磷酸化。

炎性体执行一种称为死亡的独特类型的细胞死亡。caspase-1的激活主要表现在髓样细胞中，在炎症小体传感器的下游导致卵清蛋白D（GSDMD）的裂解和激活，然后在质膜上形成裂解孔。最近，CARD8被鉴定为一种新型的炎症小体传感器，可在抑制二肽基肽酶（DPP）后触发髓样白血病细胞的焦磷酸化。在这里，我们显示使用Val-boroPro阻断DPP会触发原代人CD4和CD8 T细胞的细胞溶解形式的裂解，而其他典型的炎性体刺激物则没有活性。这种细胞死亡显示了焦细胞凋亡的形态和生化特征。通过遗传分解原代T细胞中的候选成分，我们确定该反应取决于CARD8-caspase-1-GSDMD轴。此外，DPP9构成了相关的DPP抑制CARD8激活。有趣的是，这种CARD8诱导的焦磷酸化途径只能参与静息，而不能参与活化的T细胞。总之，这些结果扩大了炎性体信号传导和相关的焦磷酸化细胞死亡与适应性免疫系统的核心参与者T细胞的相关性。