Researchers have shown that T cells produced the neurotransmitter acetylcholine to affect blood vessel dilation, which helped them control chronic infections.

The work was published in the Feb. 8, 2019, issue of Science.

The research explains the otherwise puzzling observation, made by the same team a few years back, that acetylcholine, which is a neurotransmitter, is made by B and T cells as well as neurons.

Under baseline conditions, a few percent each of B and T cells express the enzyme choline acetyltransferase (ChAT), which catalyzes a key step of the formation of acetylcholine.

Acetylcholine is one of the workhorse transmitters of the nervous system. It is used for signaling at the neuromuscular junction, sending the brain's commands to the muscles.

When scientists at the University of Toronto and the Feinstein Institute of Medical Research first reported that B and T cells produced acetylcholine as well, the findings were considered "a curiosity" by most of their colleagues, Tak Mak told BioWorld MedTech.

Mak is a senior scientist at the Princess Margaret Cancer Centre, and the senior author of the Science paper.

When they first identified them, the cells were more than a curiosity to Mak and his colleagues. A few years after discovering the acetylcholine-producing T cells, they showed that those cells affected blood pressure, with mice lacking the cells having higher blood pressure than their littermates whose T cells produced acetylcholine.

In the work now published in Science, Mak and his colleagues showed that those effects on blood pressure, in turn, helped T cells control chronic viral infection.

"When we infected a mouse with an acute virus, the number of [helper] T cells making acetylcholine jumped to over 50 percent . . . sometimes 80 percent. And [ChAT-expressing killer] T cells went from zero to 50 percent," Mak recounted.

All that acetylcholine, in turn, lowered blood pressure in infected mice, slowing down blood flow enough to make it easier for T cells to exit the bloodstream, where they patrol under normal circumstances, and get into tissues, where their actual work is done during an infection.

In acute infections, the uptick in acetylcholine-producing cells was short-lived. But "when you infect a mouse with a chronic virus, not an acute virus, the number of these cells stays up and does not come down," showing that acetylcholine production played a role in controlling long-term infections.

The team showed that in the face of a normally acute infection, mice whose T cells lacked the ability to produce acetylcholine were "helpless. [They] cannot clear the virus in months. The T cells cannot get out of the blood and into the infected tissues," Mak said.

In addition to ChAT, interleukin-21 (IL-21) was a critical factor to enable T cells to enter tissues. The cytokine enhanced acetylcholine production, and it possibly plays a role in acetylcholine release as well.

Beyond the specifics of viral infection, the work could impact multiple other disease areas.

One possible application is in tumor biology, where a major current goal is to sensitize tumors to checkpoint inhibition.

"In 20 to 30 percent of tumors, T cells can't get in" to attack the tumors, Mak said.

In such so-called excluded phenotypes, T cells clearly recognize that there is something amiss, and home to the tumor but do not enter it, staying at the borders instead. There are a number of possible reasons for that, and the work now published in Science adds another one, Mak said. "We surmise that [T cells can't] go in because they do not have the neurotransmission signal."

The work could also explain a long-standing puzzle with respect to chronic diseases with an inflammatory component – which is pretty much all of them.

In chronic conditions that include cardiovascular disease, lung fibrosis, diabetic nephropathy and chronic infections, he said, "pathologists have noticed for over a century that when there is inflammation, it is not only immune cells but new nerves growing."

However, the phenomenon has been little followed up on – "even cystic fibrosis, where there is evidence that the nerves may play a role," he said.