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 determined. We previously showed 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+CD44hiCD62Llo 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, compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT and endothelial cells increased endothelial cell levels of phosphorylated endothelial nitric oxide synthase, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasorelaxant 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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Rosas-Ballina, M. et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 334, 98–101 (2011).
Furchgott, R.F. The pharmacology of vascular smooth muscle. Pharmacol. Rev. 7, 183–265 (1955).
Furchgott, R.F. & Zawadzki, J.V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 373–376 (1980).
Fleming, I. & Busse, R. NO: the primary EDRF. J. Mol. Cell. Cardiol. 31, 5–14 (1999).
Mulvany, M.J. & Aalkjaer, C. Structure and function of small arteries. Physiol. Rev. 70, 921–961 (1990).
Andersson, U. & Tracey, K.J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30, 313–335 (2012).
Olofsson, P.S. et al. α7 nicotinic acetylcholine receptor (α7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol. Med. 18, 539–543 (2012).
Tallini, Y.N. et al. BAC transgenic mice express enhanced green fluorescent protein in central and peripheral cholinergic neurons. Physiol. Genomics 27, 391–397 (2006).
Eden, E., Navon, R., Steinfeld, I., Lipson, D. & Yakhini, Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10, 48 (2009).
Huang, W., Sherman, B.T. & Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57 (2009).
Huang, W., Sherman, B.T. & Lempicki, R.A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13 (2009).
Kanehisa, M., Goto, S., Sato, Y., Furumichi, M. & Tanabe, M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 40, D109–D114 (2012).
Heng, T.S. & Painter, M.W. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).
Mingueneau, M. et al. The transcriptional landscape of αβ T cell differentiation. Nat. Immunol. 14, 619–632 (2013).
Dimmeler, S. et al. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399, 601–605 (1999).
Huang, P.L. et al. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 377, 239–242 (1995).
Laurat, E. et al. In vivo downregulation of T helper cell 1 immune responses reduces atherogenesis in apolipoprotein E-knockout mice. Circulation 104, 197–202 (2001).
Robertson, A.K. et al. Disruption of TGF-beta signaling in T cells accelerates atherosclerosis. J. Clin. Invest. 112, 1342–1350 (2003).
Guzik, T.J. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449–2460 (2007).
Harrison, D.G. et al. Inflammation, immunity, and hypertension. Hypertension 57, 132–140 (2011).
Matrougui, K. et al. Natural regulatory T cells control coronary arteriolar endothelial dysfunction in hypertensive mice. Am. J. Pathol. 178, 434–441 (2011).
Marvar, P.J. & Harrison, D.G. Stress-dependent hypertension and the role of T lymphocytes. Exp. Physiol. 97, 1161–1167 (2012).
Olofsson, P.S., Rosas-Ballina, M., Levine, Y.A. & Tracey, K.J. Rethinking inflammation: neural circuits in the regulation of immunity. Immunol. Rev. 248, 188–204 (2012).
Kawashima, K., Fujii, T., Moriwaki, Y., Misawa, H. & Horiguchi, K. Reconciling neuronally and nonneuronally derived acetylcholine in the regulation of immune function. Ann. N Y Acad. Sci. 1261, 7–17 (2012).
Bearden, S.E., Payne, G.W., Chisty, A. & Segal, S.S. Arteriolar network architecture and vasomotor function with ageing in mouse gluteus maximus muscle. J. Physiol. (Lond.) 561, 535–545 (2004).
Fujimoto, K., Matsui, M., Fujii, T. & Kawashima, K. Decreased acetylcholine content and choline acetyltransferase mRNA expression in circulating mononuclear leukocytes and lymphoid organs of the spontaneously hypertensive rat. Life Sci. 69, 1629–1638 (2001).
Tracey, K.J. Shock medicine. Sci. Am. 312, 28–35 (2015).
Olofsson, P.S. A stimulating concept: bioelectronic medicine in inflammatory disease. Bioelectron. Med. 1, 30–33 (2015).
Edgar, R., Domrachev, M. & Lash, A.E. Gene Expression Omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 30, 207–210 (2002).
Lee, P.P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).
Krump-Konvalinkova, V. et al. Generation of human pulmonary microvascular endothelial cell lines. Lab. Invest. 81, 1717–1727 (2001).
Ye, X., Ding, J., Zhou, X., Chen, G. & Liu, S.F. Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J. Exp. Med. 205, 1303–1315 (2008).
Ahmed, M.N. et al. Extracellular superoxide dismutase overexpression can reverse the course of hypoxia-induced pulmonary hypertension. Mol. Med. 18, 38–46 (2012).
Dong, Q.G. et al. A general strategy for isolation of endothelial cells from murine tissues. Characterization of two endothelial cell lines from the murine lung and subcutaneous sponge implants. Arterioscler. Thromb. Vasc. Biol. 17, 1599–1604 (1997).
Carvalho, B.S. & Irizarry, R.A. A framework for oligonucleotide microarray preprocessing. Bioinformatics 26, 2363–2367 (2010).
Luo, J. et al. A comparison of batch effect removal methods for enhancement of prediction performance using MAQC-II microarray gene expression data. Pharmacogenomics J. 10, 278–291 (2010).
Smyth, G.K. in Bioinformatics and Computational Biology Solutions using R and Bioconductor (eds. Gentleman, R., Carey, V., Dudoit, S., Irizarry, R. & Huber, W.) 397–420 (Springer, New York, 2005).
Eden, E., Lipson, D., Yogev, S. & Yakhini, Z. Discovering motifs in ranked lists of DNA sequences. PLoS Comput. Biol. 3, e39 (2007).
We thank the flow cytometry facility at the Feinstein Institute, the laboratory of C. Benoist at Harvard Medical School for assistance, and G.K. Hansson for comments. We thank C. James Kirkpatrick (Institute of Pathology, Johannes-Gutenberg University, Mainz, Germany), who kindly provided PMEC-ST1.6R cells. This work benefitted from the data assembled by the ImmGen consortium. This work was supported by the following grants: NIH, NIGMS RO1 GM57226 to K.J.T., NIGMS RO1 GM098446 to H.Y. and NIGMS RO1GM089807 to K.J.T. and V.A.P., VR 2013-3003 to A.A., NIAID R01 029690 to T.L.R., Canadian Institutes for Health Research FRN 119339 to P.H.B., and Knut and Alice Wallenberg's Foundation 2014.0212, The Swedish Heart-Lung Foundation 20150767 and Svenska Läkaresällskapet to P.S.O. Jurkat cells (originally obtained from ATCC) were a gift from C. Chu, The Feinstein Institute for Medical Research. eNOS-deficient mice were provided by J. Lundberg and E. Weitzberg, Karolinska Institutet, Stockholm, Sweden.
The authors declare no competing financial interests.
Supplementary Figures 1–18 and Supplementary Tables 1 and 5 (PDF 1855 kb)
Included samples (XLSX 21 kb)
ChAT expr values (XLS 38 kb)
Subsets from the Immgen dataset included in the principal component analysis of splenic immune cell subsets (XLS 26 kb)
About this article
Cite this article
Olofsson, P., Steinberg, B., Sobbi, R. et al. Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase. Nat Biotechnol 34, 1066–1071 (2016). https://doi.org/10.1038/nbt.3663
Current Molecular Biology Reports (2022)
Natural killer cells, gamma delta T cells and classical monocytes are associated with systolic blood pressure in the multi-ethnic study of atherosclerosis (MESA)
BMC Cardiovascular Disorders (2021)
Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension
Molecular Medicine (2021)
Nature Reviews Drug Discovery (2021)
Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19
Nature Biotechnology (2021)