Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase

Abstract

Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been defined. We previously described that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals1. Here we show that these CD4+ CD44high CD62Llow T helper cells by gene expression are a distinct T cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure and echocardiographic assessment consistent with increased vascular resistance as compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT increased endothelial cell levels of phosphorylated eNOS, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasodilator nitric oxide. The isolation and characterization of CD4 TChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.

Mechanisms and Therapeutic Relevance of Neuro-immune Communication

“…T cells have been shown to play a role in atherosclerosis, and chronic vascular inflammation, mediating chronic hypertension. These current findings (Olofsson et al, 2016) suggest that a dysregulation of ChAT + CD4 + T cells could also contribute to the development of hypertensive phenotype. Acetylcholine producing CD4 + T cells in spleen, and possibly other tissues, are regulated by neural signals traveling in the vagus and splenic nerves (Rosas-Ballina et al, 2011), which provides a regulatory mechanism that can be therapeutically explored.…”

“…The discovery of the inflammatory reflex generated a great deal of interest in studying the vagus nerve-splenic nerve axis in the regulation of immune function in a variety of conditions, including antibody secretion following exposure of B cells to blood-borne antigen and modulating cell trafficking and splenic lymphoid architecture (Mina-Osorio et al, 2012), IBD (Ji et al, 2013; Munyaka et al, 2014), renal ischemia-reperfusion injury (Inoue et al, 2016), and T cell activation and egression from the spleen in experimental hypertension (Carnevale et al, 2016). In addition, research initially performed to further characterize T-ChAT cells led to the important discovery that a specific subset of these cells mediate blood pressure regulation (Olofsson et al, 2016). Although it is known that acetylcholine causes vasodilation resulting in decreased blood pressure, blood vessel innervations are almost exclusively catecholaminergic and the origin of acetylcholine associated causing endothelium-derived relaxation has remained enigmatic for a long time.…”

“…Although it is known that acetylcholine causes vasodilation resulting in decreased blood pressure, blood vessel innervations are almost exclusively catecholaminergic and the origin of acetylcholine associated causing endothelium-derived relaxation has remained enigmatic for a long time. Importantly, selective ablation of ChAT expression in CD4 + T cells in mice results in hypertensive phenotype that can be reversed by direct infusion of Jurkat T cells overexpressing ChAT (Olofsson et al, 2016). This observation indicates the homeostatic role of ChAT + CD4 + T cells in vasorelaxation and regulation of blood pressure.…”

Cholinergic neuron‐like D‐U87 cells promote polarization of allergic rhinitis T‐helper 2 cells

“…Although increasing evidence indicates the importance of parasympathetic nerves in the immune function of patients with other systematic diseases, studies of neuroimmune regulation in the field of AR have rarely been reported. 11,16,[21][22][23] In the present study, by establishing an in-vitro neuroimmune coculture model of D-U87 neurons and CD4 + T cells, we observed that cholinergic neuron-like D-U87 cells promoted the polarization of CD4 + T cells from patients with AR toward Th2 cells, and inhibition of the cholinergic activity of D-U87 cells by IB decreased the preferential Th2 polarization by modulating Akt signaling. To facilitate investigation of the role of cholinergic nerve function in patients with AR, an in-vitro cholinergic neuron model must be established.…”

Clinical studies and anti‐inflammatory mechanisms of treatments

“…Activation of endothelial cholinergic receptors promotes release of nitric oxide that reduces blood pressure by relaxing vascular smooth muscle cells . CD4 T ChAT are found in murine blood, and mice deficient in CD4 T ChAT show significantly increased blood pressure and their cardiovascular physiology is consistent with an increased systemic vascular resistance . These observations indicate that CD4 T ChAT regulates blood pressure by providing a cholinergic signal to vascular endothelial cells, and it is conceivable that neurotransmitter‐releasing immune cells may interact with nerves and organs to regulate physiology in additional ways not yet discovered.…”