Swedish Study Finds That T Cells In Blood Produce Acetylcholine Which May Aid In Controlling Blood Pressure And Inflammation

 A new study led by researchers from Karolinska Institutet and the Karolinska University Hospital-Sweden has found that T cells in human blood produce acetylcholine which may aid in controlling blood pressure and inflammation.


 
The study findings also have a relevance in the COVID-19 era as the study found a potential link between these immune cells in critically ill patients and the risk of mortality.
 
Typically, endothelial dysfunction and diminished vasodilation are connected with unfavorable cardiovascular events. T lymphocytes producing choline acetyltransferase (ChAT), the enzyme responsible for creating the vasorelaxant acetylcholine (ACh), control vasodilation and are essential to the cholinergic anti-inflammatory pathway in an inflammatory reflex in mice.
 
In this new research, the study team discovered that human T cell ChAT mRNA expression was triggered by T cell activation through the PI3K signaling pathway. The study team determined that ChAT mRNA expression was initiated by the reduction of RE-1 Silencing Transcription factor (REST)-mediated methylation of the ChAT promoter, and GATA3 upregulated ChAT mRNA expression levels in human T cells. Functionally, T cell-derived ACh enhanced endothelial nitric oxide-synthase activity, encouraged vasorelaxation, and decreased vascular endothelial activation while supporting barrier integrity through a cholinergic process.
 
Additionally, the researchers found a correlation between survival in a group of patients with severe circulatory failure and the relative frequency of ChAT +CD4+ T cells in their blood.
 
These study findings on ChAT+ human T cells establish a mechanism for cholinergic immune regulation of vascular endothelial function in human inflammation. In this study, we identified primary ChAT+ T cells in patients and the regulatory mechanisms governing ChAT expression in T cells. Notably, cholinergic signals from T cells modulated vascular endothelial function in vitro.
 
The study findings were published in the peer reviewed journal: PNAS.
https://www.pnas.org/doi/10.1073/pnas.2212476120
 
Acetylcholine is known to regulate blood flow, but the origin of acetylcholine in human blood has remained uncertain. The study team discovered that specific T cells in human blood can produce acetylcholine, which may aid in controlling blood pressure and inflammation.
 
The study findings also suggest a potential link between these immune cells in critically ill patients and the risk of mortality.
 
The regulation of blood flow by acetylcholine has long been established, as evidenced by the 1998 Nobel Prize in Physiology or Medicine.
 
However, the sources of acetylcholine in human blood have been ambiguous.
 
Previous research, including studies by the current study team at Karolinska Institutet in Sweden, has indicated that a particular type of immune cell called ChAT+ T cells can generate acetylcholine and influence endothelial cells in the blood vessels of mice. The existence of these T cells in humans, though, was uncertain.
 
Co-first author, Dr Laura Tarnawski, an assistant professor at the Department of Medicine (Solna), Karolinska Institutet told Thailand t-size:16px">Medical News, "We have now demonstrated that human T cells can also release acetylcholine. This supports earlier findings in various model systems and may contribute to the development of therapies for cardiovascular and inflammatory diseases."
 
While acetylcholine also serves as a vital neurotransmitter in the brain and nervous system, the study team are particularly intrigued by its role in inflammation.
 
Co-first author, Dr Vladimir Shavva, assistant professor at the same department commented, "We're interested in understanding how the brain communicates with the immune system, a topic we still know relatively little about. Our new study reveals that immune cells can secrete acetylcholine in the blood, which can help regulate inflammation within blood vessels."

The study findings were derived from analyses of blood samples from healthy donors.
 
The study team also examined 33 patients with severe circulatory failure who had been admitted to intensive care, and discovered that higher relative blood levels of ChAT+ T cells were linked to a reduced risk of death.
 
Principal investigator, Professor Dr Peder Olofsson, senior researcher at the Department of Medicine (Solna) added, "Our study findings hold clinical significance and could lead to new diagnostic and therapeutic opportunities for critically ill patients with excessive inflammation.”
 
This is the first study to date to have investigated the role of human ChAT+ T cells in regulating vascular endothelial function through cholinergic mechanisms.
 
ChAT+ T cells, which release acetylcholine, were found to promote vasorelaxation and reduce vascular endothelial activation. Although ChAT was not detected in blood T cells through qPCR or single-cell RNA sequencing data, the study suggests that acetylcholine released by activated ChAT+ T cells may be sufficient to promote NO-mediated vascular relaxation in vivo.
 
The study also found that activated ChAT+ T cells reduced vascular endothelial activation by attenuating NF-κB activation, E-selectin expression, and changes in VE-cadherin-associated cell morphology.
 
This attenuation occurred only after prolonged T cell activation, suggesting a role for ChAT+ T cells in resolving vascular inflammation. A high ChAT+CD4+ cell relative frequency was associated with improved survival in circulatory failure, although the correlation should be interpreted cautiously due to the small sample size and diverse clinical backgrounds of the included patients.
 
ChAT expression in human T cells was not restricted to a specific subset, and multiple T cell lineages could induce ChAT transcription upon activation. CD4+ differentiation toward a Th2 phenotype significantly induced ChAT beyond baseline levels.
 
These study findings open up the possibility of using ChAT+CD4+ T cells for therapeutic purposes, such as pharmacologically promoting T cell ChAT expression or transfusing ex vivo expanded ChAT+CD4+ T cells.
 
In conclusion, this study reveals a previously unexplored mechanism for cholinergic regulation of vascular endothelial function, offering potential diagnostic and therapeutic applications for blood pressure and inflammation regulation. Further research is needed to validate these findings and explore the pathophysiological role of ChAT+ T cells in disease.
 
The research team now intends to investigate the presence of ChAT+ T cells in various patient groups and organs, as well as their impact on metabolic and inflammatory processes.
 
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