Teaching T Cells Where To Go: Immune-Derived Acetylcholine Facilitates Migration Into Infected Tissues

Most people think of acetylcholine as a neurotransmitter, a substance that is produced by nerve cells to relay signals between nerves as well as from nerves to muscle cells. In the brain, acetylcholine is linked to learning and attention. Recently, we have found that acetylcholine produced by certain immune cells allows them to migrate into infected tissues where they can then combat the infection, in a paper published in Science.

Although acetylcholine is made in great quantities by cholinergic neurons, it is also produced by a diverse number of organisms with no central nervous system, including bacteria, plants, and fungi. Even in animals with a central nervous system, acetylcholine can be made by numerous non-neuronal cells, creating what has been referred to as the non-neuronal cholinergic system. Included in this non-neuronal cholinergic system are immune cells, specifically T and B cells that constitute the adaptive arm of the immune response.

Expression of acetylcholine by immune cells was first described by Kevin Tracey’s group in 2006, who found that T cells producing acetylcholine could help mice suffering from sepsis survive. In sepsis, acetylcholine inhibits the systemic inflammatory response that occurs. The primary function of T cells is to combat pathogens, although a small subset of T cells exists to prevent overexuberant or inappropriate immune responses, and so it was possible that these acetylcholine-producing cells belonged to this regulatory subset. In order to identify their function, we tested the role of acetylcholine-producing T cells during a productive infection.

Interestingly, during infection, half of the T cells that recognize the virus have the machinery to produce acetylcholine, suggesting these cells are probably combating the infection, not regulating the immune response to it. We also found a specific chemical, interleukin 21 (IL-21), that is produced by the immune system during infection was necessary for these T cells to be able to produce acetylcholine. This is interesting because it is known that this chemical is absolutely critical to control infections, but we still don’t know exactly why. We used a genetic model to disrupt the machinery for acetylcholine synthesis only in the T cells, and we found that in animals where the T cells can’t make acetylcholine, they also could not control the viral infection.

The first identified function for acetylcholine was vasodilation, i.e. it makes blood vessels larger, which would decrease blood pressure. In 2016, it was shown that acetylcholine-producing T cells reduce blood pressure, indicating that these cells could induce vasodilation. During infection, dilating blood vessels is important to slow down the blood flow to allow immune cells enough time to recognize a particular tissue is infected and leave the blood vessels to go and combat the infection. We found that in animals where the T cells could not produce acetylcholine, the vasodilation that is a hallmark of immune responses to infection did not occur. As a consequence, the T cells were less able to get into the infected organs and eliminate infected cells, resulting in the failure to control the viral infection.

These findings not only identify a new mechanism by which immune cells move into tissues to eliminate infections, but these findings potentially impact on multiple areas that intersect with human health. One of the limiting factors in using immunotherapy to combat tumors is getting immune cells to penetrate the tumor, and it is known that treatment with IL-21 enhances the immune response to tumors. It is possible then that these acetylcholine-producing T cells are more effective at killing tumors. These data may also provide some indications for how we could restrict immune infiltration in organs during autoimmunity.