Sympathetic Innervation Promotes Bone Marrow Homing of Specific CD8+ Effector Memory T Cells in Hypertension

Abstract

We have recently identified a critical role of hypertension‐specific effector memory T lymphocytes (TEM cells) in the blood pressure elevation and renal dysfunction caused by repeated hypertensive stimuli. Formed during an initial immune challenge, TEM cells reside in the bone marrow (BM) in a quiescent state for prolonged periods, and can be reactivated upon re‐exposure to the hypertensive stimulus. Hypertension is associated with increased sympathetic outflow. We therefore hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension‐specific TEM cells in the BM. We performed unilateral superior cervical ganglionectomy (SCGx) in wild‐type C57BL/6 mice, causing selectively sympathectomy of the forelimb on the surgical side. After recovery, mice received Ang II infusion for two weeks. To determine the changes of T cells in the BM that were specific to hypertension, 5×106 BM cells were isolated from either the SCGx or control limbs, loaded with proliferation marker CFSE, and co‐cultured with 0.5×106 splenic dendritic cells isolated from another Ang II‐infused mouse. We found 30% less CD8+ T cell proliferation in the SCGx BM compared to control side (1.9±0.2 vs. 2.8±0.1×104, p<0.001), but no difference in CD4+ T cells. To further study the effect of sympathetic nerves on BM T cell homing, 1×107 pan T cells were isolated from CD45.2+ wild‐type mice after Ang II infusion and adoptively transferred to CD45.1 mice that had previously undergone unilateral SCGx. Flow cytometry indicated that 7 days after transfer, 25% fewer CD8+ TEM cells from the hypertensive donors homed to the SCGx BM compared to the innervated BM (5.3±0.8 vs. 8.1±1.5 per 104 total T cells, p<0.05), suggesting that sympathetic nerves regulate CD8+ TEM homing in the bone marrow at baseline condition. To study enhanced local sympathetic nerve activity in BM observed in hypertension, excitatory DREADD (designed receptor exclusively activated by designed drug) was expressed in the SCG on one side of mice by microinjection of adeno‐associated viral vector. Two weeks later, the animals received pan‐T cells adoptively transferred from hypertensive donors, and the specific ligand clozapine‐N‐oxide for DREADD was given in drinking water for 7 days. In contrast to denervation, augmenting sympathetic nerve activity increased CD8+ TEM homing by ~50% compared to the baseline level (14.9±2.7 vs. 9.3±2.3 per 104 total T cells, p<0.01). These data define a novel role of sympathetic nerves in regulation of memory T cell trafficking in hypertension. Adrenergic blockade may be beneficial in disrupting survival of these injurious T cells, and thus might provide protection against repeated hypertensive stimuli known cause their reactivation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.