Rationale: Effector memory T lymphocytes (TEM cells) exacerbate hypertension in response to repeated hypertensive stimuli. These cells reside in the bone marrow for prolonged periods and can be reactivated upon re-exposure to the hypertensive stimulus. Objective: Because hypertension is associated with increased sympathetic outflow to the bone marrow, we hypothesized that sympathetic nerves regulate accumulation and reactivation of bone marrow residing hypertension-specific TEM cells. Methods and Results: Using unilateral superior cervical ganglionectomy in wild-type C57BL/6 mice, we showed that sympathetic nerves create a bone marrow environment that supports residence of hypertension-specific CD8+ T cells. These cells, defined by their proliferative response upon co-culture with dendritic cells from angiotensin II infused mice, were reduced in denervated compared to innervated bone of angiotensin II-infused mice. Adoptively transferred CD8+ T cells from angiotensin II-infused mice preferentially homed to innervated compared to denervated bone. In contrast, ovalbumin responsive T cells from OT-I mice did not exhibit this preferential homing. Increasing superior cervical ganglion activity by activating Gq-coupled DREADD (designer receptor exclusively activated by designer drug) augmented CD8+ TEM bone marrow accumulation. Adoptive transfer studies using mice lacking β2 adrenergic receptors (β2AR) indicate that β2AR in the bone marrow niche, rather than T cell β2AR is critical for TEM cell homing. Inhibition of global sympathetic outflow using Gi-coupled DREADD injected into the rostral ventrolateral medulla or treatment with a β2AR antagonist reduced hypertension specific CD8+ TEM cells in the bone marrow and reduced the hypertensive response to a subsequent response to low dose angiotensin II. Conclusions: Sympathetic nerves contribute to the homing and survival of hypertension-specific TEM cells in the bone marrow after they are formed in hypertension. Inhibition of sympathetic nerve activity and β2AR blockade reduces these cells and prevents the blood pressure elevation and renal inflammation upon re-exposure to hypertension stimuli.

中文翻译：

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记忆T细胞归巢和高血压过敏的交感增强。

原理：效应记忆T淋巴细胞（TEM细胞）对反复的高压刺激会加剧高血压。这些细胞长期存在于骨髓中，并且在再次暴露于高血压刺激后可以重新激活。目的：由于高血压与交感神经向骨髓的流出增加有关，因此我们假设交感神经调节驻留在高血压特异性TEM细胞中的骨髓的积累和再激活。方法和结果：在野生型C57BL / 6小鼠中使用单侧上颈神经节切除术，我们发现交感神经创建了一个支持高血压特异性CD8 + T细胞驻留的骨髓环境。这些细胞的定义是与输注血管紧张素II的树突状细胞共培养时的增殖反应，与经血管紧张素II注入的小鼠的神经支配相比，神经支配体的减少。与神经支配的骨骼相比，来自血管紧张素II输注小鼠的过继转移的CD8 + T细胞优先归巢于神经支配。相反，来自OT-1小鼠的卵清蛋白应答性T细胞没有表现出这种优先归巢。通过激活Gq偶联的DREADD（由设计药物独家激活的设计受体）来增加优越的颈神经节活动，从而增加CD8 + TEM骨髓的积累。使用缺乏β2肾上腺素能受体（β2AR）的小鼠进行的过继转移研究表明，骨髓生境中的β2AR而非T细胞β2AR对于TEM细胞归巢至关重要。使用注射入延髓腹侧延髓的Gi偶联DREADD抑制整体交感性流出或使用β2AR拮抗剂治疗可降低骨髓中的高血压特异性CD8 + TEM细胞，并降低对随后对低剂量血管紧张素II的反应的高血压反应。结论：交感神经在高血压形成后有助于骨髓中高血压特异性TEM细胞的归巢和存活。交感神经活性的抑制和β2AR阻滞减少了这些细胞，并在再次暴露于高血压刺激下防止了血压升高和肾脏发炎。交感神经在高血压中形成后，有助于骨髓中高血压特异性TEM细胞的归巢和存活。交感神经活性的抑制和β2AR阻滞减少了这些细胞，并在再次暴露于高血压刺激下防止了血压升高和肾脏发炎。交感神经在高血压中形成后，有助于骨髓中高血压特异性TEM细胞的归巢和存活。交感神经活性的抑制和β2AR阻滞减少了这些细胞，并在再次暴露于高血压刺激下防止了血压升高和肾脏炎症。