CARD8 inflammasome activation triggers pyroptosis in human T cells.
CARD8 inflammasome activation triggers pyroptosis in human T cells.
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DOI：
10.15252/embj.2020105071
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发表时间：
2020-10-01
期刊：
影响因子：
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通讯作者：
Hornung V
中科院分区：
文献类型：
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作者：
Linder A;Bauernfried S;Cheng Y;Albanese M;Jung C;Keppler OT;Hornung V
炎性小体执行一种称为焦亡的独特细胞死亡。caspase‐1在炎性体传感器下游的激活导致气真皮蛋白D （GSDMD）的裂解和激活，然后在质膜上形成一个裂解孔。最近，CARD8被鉴定为一种新的炎症小体传感器，通过抑制二肽基肽酶（DPP）触发髓系白血病细胞的焦亡。在这里，我们发现使用Val‐boroPro阻断DPPs会在原发人CD4和CD8 T细胞中引发细胞死亡的溶解形式，而其他原型炎性体刺激则没有活性。这种细胞死亡表现出焦亡的形态和生化特征。通过对原代T细胞中的候选成分进行基因解剖，我们发现这种反应依赖于CARD8 - caspase - 1 - GSDMD轴。此外，DPP9构成了抑制CARD8激活的相关DPP。有趣的是，这种CARD8诱导的焦亡途径只在静止状态下发生，而在活化的T细胞中不发生。总之，这些结果扩大了炎性小体信号和相关的热噬细胞死亡与T细胞的相关性，T细胞是适应性免疫系统的核心参与者。炎性细胞死亡，在髓系免疫细胞中得到了最好的研究，也可以在T细胞中特异性地依赖CARD8炎性小体/caspase‐1/gasdermin‐D轴触发。
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. Inflammatory cell death, best studied in myeloid immune cells, can also be triggered in T cells depending specifically on the CARD8 inflammosome/caspase‐1/gasdermin‐D axis.