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Circ Res. 2020 Jan 13. doi: 10.1161/CIRCRESAHA.119.314758. [Epub ahead of print]

Sympathetic Enhancement of Memory T Cell Homing and Hypertension Sensitization.

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Clinical Pharmacology, Medicine, Vanderbilt University Medical Center, UNITED STATES.
Integrative Biology and Physiology, University of Minnesota, UNITED STATES.


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.


T-cells; angiotensin II; dendritic cells

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