TRM maintenance is regulated by tissue damage via P2RX7
TRM maintenance is regulated by tissue damage via P2RX7
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DOI：
10.1126/sciimmunol.aau1022
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发表时间：
2018-12-01
影响因子：
24.8
通讯作者：
van Lier, Rene A. W.
中科院分区：
文献类型：
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作者：
Stark, Regina;Wesselink, Thomas H.;van Lier, Rene A. W.
组织驻留记忆T细胞（T-RM）是非循环免疫细胞，有助于抵抗再感染的第一道局部防御。它们在病原体遭遇的热点的位置经常使T-RM暴露于组织损伤。这种暴露于T-RM信号的历史是T-RM介导的免疫的一个重要方面，迄今为止一直被忽视。RNA分析显示，来自肝脏和小肠的T-RM表达P2 RX 7，这是一种由细胞外核苷酸（ATP，NAD（+））触发的损伤/损伤相关分子模式（DAMP）受体。我们证实，在不同的感染模型中，P2 RX 7蛋白在CD 8（+）T-RM中表达，但在循环T细胞（T-CIRC）中不表达。在常规分离肝淋巴细胞过程中诱导的组织损伤导致P2 RX 7活化并导致T-RM的选择性细胞死亡。外源性NAD（+）在体内激活P2 RX 7导致T-RM的特异性消耗，同时保留T-CIRC。这种作用在P2 RX 7缺陷小鼠和P2 RX 7阻断后不存在。TCR触发下调P2 RX 7表达，使T-RM对NAD诱导的细胞死亡具有抗性。对乙酰氨基酚诱导的肝损伤过程中无菌组织损伤对P2 RX 7的生理触发导致野生型T细胞中先前获得的病原体特异性局部TRM的丧失，但在P2 RX 7 KO T细胞中则不然。我们的研究结果突出了P2 RX 7介导的信号传导作为调节T-RM维持的关键途径。在感染和组织损伤过程中释放的细胞外核苷酸可以局部消耗T-RM，并为新的和感染相关的特异性释放壁龛。这表明组织损伤的识别促进了组织小生境中抗原特异性T-RM超过旁观者T-RM的持续存在。
Tissue-resident memory T cells (T-RM) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes T-RM to tissue damage. This history of danger-signal exposure is an important aspect of T-RM-mediated immunity that has been overlooked so far. RNA profiling revealed that T-RM from liver and small intestine express P2RX7, a damage/danger-associated molecular pattern (DAMP) receptor that is triggered by extracellular nucleotides (ATP, NAD(+)). We confirmed that P2RX7 protein was expressed in CD8(+) T-RM but not in circulating T cells (T-CIRC) across different infection models. Tissue damage induced during routine isolation of liver lymphocytes led to P2RX7 activation and resulted in selective cell death of T-RM. P2RX7 activation in vivo by exogenous NAD(+) led to a specific depletion of T-RM while retaining T-CIRC. The effect was absent in P2RX7-deficient mice and after P2RX7 blockade. TCR triggering down-regulated P2RX7 expression and made T-RM resistant to NAD-induced cell death. Physiological triggering of P2RX7 by sterile tissue damage during acetaminophen-induced liver injury led to a loss of previously acquired pathogen-specific local TRM in wild-type but not in P2RX7 KO T cells. Our results highlight P2RX7-mediated signaling as a critical pathway for the regulation of T-RM maintenance. Extracellular nucleotides released during infection and tissue damage could deplete T-RM locally and free niches for new and infection-relevant specificities. This suggests that the recognition of tissue damage promotes persistence of antigen-specific over bystander T-RM in the tissue niche.