Cholinergic regulation of vascular endothelial function by human ChAT <sup>+</sup> T cells
Laura Tarnawski, Vladimir S. Shavva, Eric J. Kort, Zhengbing Zhuge, Ingrid Nilsson, Alessandro L. Gallina, David Martínez-Enguita, Benjamin Heller Sahlgren, Matthew Weiland, April S. Caravaca, Staffan Schmidt, Ping Chen, Katarina Abbas, Fuhua Wang, Ahmed Osman, Michael Eberhardson, Anna Färnert, Eddie Weitzberg, Mika Gustafsson, Ján Kehr, Stephen Malin, Henrik Hult, Mattias Carlström, Stefan Jovinge, Peder S. Olofsson
Abstract
Endothelial dysfunction and impaired vasodilation are linked with adverse cardiovascular events. T lymphocytes expressing choline acetyltransferase (ChAT), the enzyme catalyzing biosynthesis of the vasorelaxant acetylcholine (ACh), regulate vasodilation and are integral to the cholinergic antiinflammatory pathway in an inflammatory reflex in mice. Here, we found that human T cell ChAT mRNA expression was induced by T cell activation involving the PI3K signaling cascade. Mechanistically, we identified that ChAT mRNA expression was induced following the attenuation of RE-1 Silencing Transcription factor REST-mediated methylation of the ChAT promoter, and that ChAT mRNA expression levels were up-regulated by GATA3 in human T cells. In functional experiments, T cell-derived ACh increased endothelial nitric oxide-synthase activity, promoted vasorelaxation, and reduced vascular endothelial activation and promoted barrier integrity by a cholinergic mechanism. Further, we observed that survival in a cohort of patients with severe circulatory failure correlated with their relative frequency of ChAT + CD4 + T cells in blood. These findings on ChAT + human T cells provide a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation.