ヒトChAT+ T細胞によるコリン作動性血管内皮機能制御機構 Cholinergic regulation of vascular endothelial function by human ChAT+ 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,Fu-Hua Wang,Osman Ahmed,Michael Eberhardson,Anna Färnert,Eddie Weitzberg,Mika Gustafsson,Jan Kehr,Stephen G. Malin,Henrik Hult,Mattias Carlström ,Stefan Jovinge,Peder S. Olofsson
Proceedings of the National Academy of Sciences Published:March 29, 2023
ACh-releasing choline acetyltransferase (ChAT)+ T cells promote vasodilation and regulate blood pressure in mice, but human ChAT+ T cells and the molecular mechanisms by which ChAT-expression is regulated remain undefined. In this study, we identify primary ChAT+ T cells in patients and regulatory mechanisms for ChAT expression in T cells. Interestingly, cholinergic signals from T cells regulated vascular endothelial function in vitro.
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.