Gut Microbes May Assist in Educating Immune System Early in Development

A study published in Nature may document a previously unknown interaction between gut microbes and the thymus, an immune system organ. The study was designed to examine what happens to microbe-specific T cells when mice are exposed as young pups to a common gut microbe. Although the researchers hypothesized that the T cells specific to this microbe would be deleted, they instead grew in number.

The thymus's main role is "educating" T cells about which antigens in the body are self and which are non-self, according to the study. T cells that recognize self are actively culled whereas those that do not recognize self are spared. The non-self-recognizing T cells are then released into circulation where they patrol for viruses, bacteria, and other invaders.

“We were very, very surprised that when we colonized mice with gut bacteria, instead of seeing the development of regulatory T cells that calm immune reactions or loss of microbe-specific T cells, we saw an expansion of them,” said Gretchen Diehl, PhD, an immunologist in the Sloan Kettering Institute, in a press release. “As far as we are aware, this is the first time anyone has shown the thymus playing this role in the expansion of microbe-specific T cells.”

Using standard gut microbiota detection techniques, the investigators could see that bacterial DNA was showing up in the thymus, suggesting that the gut is somehow in communication with this organ via DNA. The investigators hypothesized that the bacterial DNA is being carried to the thymus by dendritic cells, which carry suspicious antigens from tissues to lymph nodes, though dendritic cells traveling from the gut to the thymus had not been previously recorded.

To track the movement of dendritic cells, the researchers took advantage of a hi-tech lab mouse engineered to make a fluorescent marker called green fluorescent protein (GFP) in its cells. When GFP-containing cells are hit with light from a laser, they change from emitting green fluorescence to emitting red. By shining the laser in the intestine of the mouse, the scientists were able to turn gut dendritic cells red and then observe the cells arriving in the mouse thymus.

“The dendritic cells are clearly migrating that whole way, which is kind of crazy,” Diehl said in the release.

According to the results of the study, the gut-to-thymus journey only happens in very young animals. The investigators did not observe the red cells appearing in the thymus of older animals.

“What we think is happening is a kind of templating on the immune system,” Diehl said in the release. “In that timeframe, the mouse immune system is very underdeveloped and the most relevant thing for it to recognize is microbes. So, it brings gut antigens to the thymus to educate the T cells about these and related dangers.”

The researchers demonstrated that the T cells that recognize the introduced bacteria also afford protection against pathogens the mice hadn't yet seen. However, their recognition of gut microbes meant that these T cells can also cause inflammation that could lead to colitis. The current goal of the study authors is to determine whether this process differs in individuals who are more susceptible to colitis.

“Do you have this happening for a more extended period of time in people with colitis?” Diehl said in the release. “Do you have it happening for less? Does it restart in someone with colitis? These are all questions we want to explore.”

REFERENCE

A delicate balance: Learning new ways that gut microbes educate the immune system [news release]. EurekAlert; May 12, 2021. Accessed May 19, 2021. https://eurekalert.org/pub_releases/2021-05/mskc-adb051221.php