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Sympathetic Nerves Promote Hypertension‐Specific CD8 + Effector Memory T Cell Homing in the Bone Marrow of Mice with Angiotensin II Infusion
Author(s) -
Xiao Liang,
Itani Hana A,
Foss Jason D,
Harrison David G
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.358.4
Subject(s) - ganglionectomy , endocrinology , medicine , bone marrow , homing (biology) , angiotensin ii , cd8 , sympathectomy , t cell , sympathetic nervous system , blood pressure , immune system , biology , immunology , pathology , ecology , alternative medicine
We have recently identified a critical role of hypertension‐specific effector memory T lymphocytes (T EM cells) in the blood pressure elevation and renal dysfunction caused by repeated hypertensive stimuli. Formed during an initial immune challenge reside, a substantial portion of T EM cells reside in the bone marrow (BM) in a quiescent state for prolonged periods, and they can be reactivated upon re‐exposure to the hypertensive stimulus. Hypertension is associated with increased sympathetic outflow. We confirmed that expression of tyrosine hydroxylase, a marker for sympathetic innervation, was increased by 70% in the BM in mice received angiotensin (Ang) II infusion (490ng/kg/min) for two weeks. We therefore hypothesized that sympathetic nerves regulate accumulation and reactivation of hypertension‐specific T EM cells in 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 from surgery, mice received Ang II infusion for two weeks. The number of T EM cells in the denervated BM following Ang II was slightly but significantly less than observed in the innervated limb as measured by flow cytometry. To determine T cells in the BM that were specific to hypertension, 5×10 6 BM cells were isolated from either the SCGx or control limbs, loaded with proliferation marker CFSE, 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 (1.8±0.1 vs. 2.6±0.3×10 4 ), but no difference in CD4 + T cells. To further study the effect of sympathetic nerves on T cell homing in BM, 1×10 7 pan T cells were isolated from wild‐type mice (w/CD45.2 allele) after Ang II infusion, and adoptively transferred into CD45.1 mice that had previously received SCGx. Flow cytometry indicated that 7 days after transfer, 25% less CD8 + T EM cells from hypertensive donors homed to the SCGx BM than the innervated BM of recipients (20.8±2.5 vs. 27.8±2.6 per 10 3 total BM cells). Similar adoptive transfer experiments were performed between CD45.1 mice and β2 adrenoreceptor deficient mice. CD8 + T EM cell homing was dramatically attenuated by 70% if the recipient was deficient of β2 receptors. We conclude that sympathetic nerves promote T EM cell homing to the BM after an initial blood pressure elevation via β2 adrenergic signaling. This may contribute to the predisposition to hypertension and end‐organ damage for prolonged periods following an initial episode of hypertension.