Non-canonical Hedgehog signaling through L-type voltage gated Ca 2+ channels controls CD8 + T cell killing
Non-canonical Hedgehog signaling through L-type voltage gated Ca 2+ channels controls CD8 + T cell killing
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通过 L 型电压门控 Ca 2 通道的非经典 Hedgehog 信号控制 CD8 T 细胞杀伤
DOI：
10.1101/2021.03.01.433424
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Hanna J
中科院分区：
文献类型：
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作者：
Hanna J
细胞毒性CD 8 +T淋巴细胞（CTL）对于针对细胞内病原体和癌症的免疫应答至关重要，并且通过靶向分泌细胞毒性颗粒来消除感染的和恶性的细胞。Hedgehog（Hh）信号转导已被证明对CTL杀伤至关重要。有趣的是，CD 8 +T细胞中的Hh信号传导不是由细胞外Hh配体诱导的，而是在T细胞受体（TCR）接合后启动的。TCR如何独立于细胞外Hh配体诱导Hh途径尚不清楚。在这里，我们表明，Hh转录因子Gli 1是必要的有效的CTL功能，并诱导下游的TCR细胞外Ca 2+内流选择性控制的L型电压门控Ca 2+通道定位在质膜。我们证明了这种Hh信号诱导的新模式独立于经典Hh通路，代表了幼稚CD 8 +T细胞中Gli 1诱导的主要机制，而CTL也可以通过MAP激酶信号激活Gli 1。重要的是，我们表明，这种L-型电压门控钙通道控制的Gli 1诱导功能所需的CTL杀伤小鼠和人类。Gli抑制剂目前正在针对各种癌症的临床试验中，我们的观察表明它们可能抑制抗肿瘤反应。显著性声明细胞毒性CD 8 +T细胞（CTL）通过靶向分泌细胞毒性颗粒杀死感染和恶性细胞。Hedgehog信号传导对于有效的CTL杀伤是关键的，并且独立于外源Hedgehog配体被T细胞受体（TCR）激活。这项研究表明，刺猬转录因子Gli 1是CTL杀伤所必需的，并确定L型电压门控Ca 2+通道（Cav 1）作为小鼠和人类CTL杀伤的重要调节因子，凭借其激活TCR下游Gli 1的能力。Cav 1-Gli 1轴独立于典型的Hedgehog信号传导。我们的工作表明，在使用Gli抑制剂时需要谨慎，目前正在试验中作为抗癌治疗药物，因为它们可能会抑制抗肿瘤反应。
Cytotoxic CD8+T lymphocytes (CTLs) are critical to the immune response against intracellular pathogens and cancer and act by eliminating infected and malignant cells through targeted secretion of cytotoxic granules. Hedgehog (Hh) signaling has been shown to be critical for CTL killing. Interestingly, Hh signaling in CD8+T cells is not induced by extracellular Hh ligands but is initiated upon T cell receptor (TCR) engagement. How the TCR induces the Hh pathway independently of extracellular Hh ligands is unknown. Here we show that the Hh transcription factor Gli1 is essential for efficient CTL function and is induced downstream of the TCR by an extracellular Ca2+influx selectively controlled by L-type voltage gated Ca2+channels localized at the plasma membrane. We demonstrate that this novel mode of Hh signaling induction is independent of the canonical Hh pathway and represents the primary mechanism of Gli1 induction in naïve CD8+T cells, while CTLs can also activate Gli1 via MAP Kinase signaling. Importantly, we show that this L-type voltage gated Ca2+channel-controlled Gli1 induction is functionally required for CTL killing in mice and humans. Gli inhibitors are currently in clinical trials against various cancers and our observations indicate that they likely inhibit the anti-tumor response.Significance statementCytotoxic CD8+T cells (CTLs) kill infected and malignant cells by targeted secretion of cytotoxic granules. Hedgehog signaling is critical for effective CTL killing and is activated by the T cell receptor (TCR) independently of exogenous Hedgehog ligands. This study shows that Hedgehog transcription factor Gli1 is required for CTL killing and identifies L-type voltage gated Ca2+channels (Cav1) as essential regulators of CTL killing in mouse and human, by virtue of their ability to activate Gli1 downstream of the TCR. This Cav1-Gli1 axis operates independently of canonical Hedgehog signaling. Our work suggests that caution is required when using Gli inhibitors, currently in trials as anti-cancer therapeutics, since they may dampen the anti-tumor response.