A16563 Sympathetic Innervation Promotes Bone Marrow Homing of Specific CD8+ Effector Memory T Cells in Hypertension

Abstract

Objectives: We have recently identified a critical role of effector memory T lymphocytes (TEM cells) in the hypertension 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. In this study, we hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension-specific TEM cells in the BM. Methods: We performed unilateral superior cervical ganglionectomy (SCGx) in mice, causing selectively sympathectomy of the forelimb on the surgical side. After recovery, mice received Ang II infusion for two weeks. To study enhanced local sympathetic nerve activity in BM observed in hypertension, excitatory DREADD was transduced in the SCG on one side of mice by microinjection of AAV vector. Results: To determine the changes of T cells in the BM that were specific to hypertension, 5 × 10^6 BM cells were isolated from either the SCGx or control limbs, and co-cultured with 0.5 × 10^6 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 but no difference in CD4+ T cells. Mice with DREADD expression in SCG received 10^7 pan-T cells adoptively transferred from hypertensive donors, and the specific ligand for DREADD was given in drinking water for 7 days. Augmented sympathetic nerve activity in BM led to ∼50% increase in the CD8+ TEM homing compared to baseline level. Conclusion: Sympathetic nerves play a crucial role in memory T cell trafficking, and this likely contributes to the predisposition to hypertension and end-organ damage for prolonged periods following an initial episode of hypertension.