Regulation of T cell responses by P2RX7

摘要 最明确的“危险”信号之一，就是提醒先天免疫系统注意细胞损伤的信号。 细胞外的ATP，触发通过嘌呤能受体P2RX7的离子流量。P2RX7在细胞周期调控中的作用 相比之下，适应性免疫系统就不那么清楚了。我们最近的研究表明，P2RX7对于 长寿命CD8 T细胞记忆的产生和维持。这涉及到P2RX7信号促进 记忆性CD8 T细胞分化过程中线粒体维持和代谢“适合性”的建立 我们还发现了持续的P2RX7信号是维持先前存在的记忆CD8 T所必需的证据 这表明这个“危险”信号被重新利用，为CD8T细胞提供了一个动态平衡生存信号。 然而，关于P2RX7信号如何影响T细胞记忆仍有许多需要了解的地方。在目标1中，我们 让我们把注意力转向CD4T细胞：虽然P2RX7对产生记忆性CD8T细胞至关重要，但某些 记忆性CD4T细胞亚群(包括滤泡辅助性中央记忆细胞)显示存活率提高 当P2rx7被消融时，我们探索了P2RX7刺激对CD_4和CD_4的不同影响的基础。 CD8记忆性T细胞亚群。在目标2中，我们探索了记忆CD8 T细胞如何能够提供自分泌 通过PAnnexin 1通道，通过“自己的”三磷酸腺苷的出口来刺激P2RX7。最后，P2RX7拥有 已被证明在生物学的另一个领域--慢性疼痛中发挥着重要作用。持续的刺激 先天免疫细胞上的P2RX7被认为与各种形式的神经病理性和炎症性有关 疼痛(与神经损伤、自身免疫性疾病、癌症等有关)和药理上的阻断 P2RX7已经在动物模型中被证明可以缓解这种慢性疼痛。这就提出了一个关键问题： 使用这种治疗性阻断是否会导致先前存在的T细胞记忆的退化--特别是， 这种治疗是否会损害CD8 T细胞对持续性病毒感染的控制。我们致力于 在目标3中，也研究了对P2RX7的定向刺激(而不是阻断)是否可以用作 改善长寿命CD8 T细胞记忆的产生和潜在地加强对 慢性病毒感染，但也可能失调的CD4T细胞记忆隔间。加在一起，这些 研究代表了一项新的、非常有意义的研究，即先天免疫触发因素是如何被吸收到 调节适应性免疫记忆，以及如何利用这一途径达到治疗目标 有可能应用于临床。

Summary One of the best defined “danger” signals, that alerts the innate immune system to cellular damage, is extracellular ATP, triggering ion flux through the purinergic receptor P2RX7. The roles of P2RX7 in the adaptive immune system, by contrast, are less clear. We recently showed that P2RX7 was essential for production and maintenance of long-lived CD8+ T cell memory. This involved P2RX7 signals promoting the establishment of mitochondrial maintenance and metabolic “fitness” in differentiating memory CD8+ T cells, but we also found evidence that sustained P2RX7 signals are needed to sustain pre-existing memory CD8+ T cells, suggesting this “danger” signal is repurposed to provide a homeostatic survival signal for CD8+ T cells. Much remains to be understood about how P2RX7 signaling influences T cell memory, however. In Aim 1, we turn our attention to CD4+ T cells: while P2RX7 is critical for generation of memory CD8+ T cells, certain subsets of memory CD4+ T cells (including follicular helper-like central memory cells), show increased survival when P2rx7 is ablated – we explore the basis for these differential effects of P2RX7 stimulation on CD4+ and CD8+ memory T cell subsets. In Aim 2, we explore how memory CD8+ T cells may be able to provide autocrine stimulation of P2RX7 through export of their “own” ATP, through the Pannexin 1 channel. Finally, P2RX7 has been shown to play an important role in another area of biology – in chronic pain. Sustained stimulation of P2RX7 on innate immune cells is thought to be responsible for various forms of neuropathic and inflammatory pain (associated with nerve damage, autoimmune diseases, cancer, etc.) and pharmacological blockade of P2RX7 has been shown in animal models to alleviate such chronic pain. This raises the key question of whether use of such therapeutic blockade leads to degradation of pre-existing T cell memory - in particular, whether such treatment would impair CD8+ T cell mediated control of persistent viral infections. We address this in Aim 3, also investigating whether directed stimulation (rather than blockade) of P2RX7 can be used as a viable way to improve the generation of long-lived CD8+ T cell memory and potentially to enhance control of chronic viral infections but may also dysregulate the CD4+ T cell memory compartment. Together, these studies represent a novel and highly significant investigation into how an innate immune trigger is co-opted into regulating adaptive immune memory, and how this pathway can be harnessed for therapeutic goals with possible application to the clinic.