The main job of the immune system is to identify the things that can make us sick. In the language of immunology, this means distinguishing “self” from “non-self”: the cells of our organs are self, while pathogenic bacteria and viruses are non-self.
But what about the billions of bacteria that live in our intestines and provide us with benefits like digesting food and making vitamins? Are they friends or enemies?
It is not just a philosophical question. An immune system that mistakes our good gut bacteria for an enemy can cause a dangerous inflammation of the intestines called colitis. Equally dangerous is an immune system that looks the other way as gut microbes spill over their assigned boundaries. Understanding how the immune system learns to make a negotiated peace with its microbial residents, called the microbiota, is therefore an important area of research.
“Right now, each of us has immune cells in our body that can recognize and attack specific members of our gut microbiota,” says Gretchen Diehl, immunologist at the Sloan Kettering Institute. “So it’s a conundrum why more of us don’t have colitis caused by these cells attacking our gut microbes.”
In an attempt to solve this puzzle, Dr. Diehl and his colleagues, including SKI postdoctoral researcher Daniel Zegarra-Ruiz and immunologist Matthew Bettini from the University of Utah, recently conducted a study using mice from laboratory to explore what happens to microbe-specific T cells (a type of immune cell) when mice are exposed as young puppies to a common gut microbe.
“We thought that maybe the T cells specific for this microbe would be eliminated from the mice, or maybe the mice would develop anti-inflammatory T cells that would protect them from developing colitis,” says Dr. Diehl. In other words, they hypothesized that the bacteria would be seen as itself.
Surprisingly, this was not the case. Not only were the microbe-specific T cells not removed, they actually increased in number. The results, published on May 12, 2021, in Nature, document a previously unknown way of gut microbes interacting with the immune system, and raise even more questions about what goes wrong with autoimmune diseases.
Scientists focused their attention on an organ of the immune system called the thymus, located in the upper part of the chest behind the breastbone. The main role of the thymus is to “educate” T cells about markers, or antigens, in the body that are self versus non-self. T cells that recognize themselves are actively eliminated while those that do not recognize themselves are spared. The unrecognizable T cells are then released into the circulation where they patrol for viruses, bacteria and other invaders.
It is believed that the education process is mainly about protecting the body from self-attacking T cells which could cause problems in the form of autoimmunity. Dr Diehl and his colleagues were surprised to find that instead of eliminating T cells that recognize gut bacteria, the thymus gave them the green light.
“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 responses or the loss of microbe-specific T cells, we saw an expansion of these, ”she said. “As far as we know, this is the first time anyone has shown that the thymus plays this role in the expansion of microbe-specific T cells.”
Then they asked: How does information about gut bacteria get to the thymus?
Using standard gut microbiota detection techniques, they were able to see that bacterial DNA appeared in the thymus, suggesting that the gut is somehow in communication with this organ via DNA. But that only raised the additional question of how this DNA got there.
One possible explanation is that bacterial DNA is carried there by immune cells called dendritic cells, whose main job is, in fact, to transport suspicious antigens from the tissues to the lymph nodes. Traveling from the intestine to the thymus had not been seen, but scientists could not rule out the possibility.
To track the movement of dendritic cells, Dr Diehl and his colleagues took advantage of a high-tech lab mouse developed by Kat Hadjantonakis’ lab at MSK. The mouse was designed to make a fluorescent marker called green fluorescent protein (GFP) in its cells. When cells containing GFP are struck by light from a laser, they switch from emitting green fluorescence to emitting red. By shining the laser into the mouse’s gut, scientists could turn gut dendritic cells red, then watch and see if any red blood cells made their way into the mouse’s thymus. Indeed, they did.
“Dendritic cells clearly migrate this way, which is kind of crazy,” says Dr. Diehl.
A temporary window
Travel from the intestine to the thymus only occurs in very young animals. When scientists looked at older animals, they didn’t see red blood cells appear. They also did not find any gut microbe DNA in the thymus or expansion of specific T cells in the gut.
What could be the purpose of this gut-thymus trafficking that only occurs during a specific window of development in mice?
“What we think is happening is kind of a model on the immune system,” says Dr Diehl. “During this period, the mouse’s immune system is very underdeveloped and the most relevant thing to recognize is microbes. Thus, it supplies intestinal antigens to the thymus gland to educate T cells about these dangers and the associated dangers. “
As proof of this possibility, they showed that the T cells that recognize introduced bacteria also offer protection against pathogens that mice had not yet seen. But because they recognize gut microbes, these T cells can also cause inflammation that can lead to colitis.
What scientists next want to know is whether this process differs in people more susceptible to colitis.
Dr. Diehl wonders, “Does it happen for a longer period of time in people with colitis? Does it happen for less? Does it start again in someone with colitis? These are all questions we want to explore. “
This work was supported by the National Institutes of Health (grants R01AI136963, R01AI125264, R01DK114456, R01AI130152, R01 DK114252, P30 CA125123 and S10 RR024574), the Kleberg Foundation, the Rainin Foundation and an award from the Leukemia and Lymphoma Society Scholar Society.