Loads of times, I have talked about how our microbiomes are the earliest instructors for our immune systems, teaching how to distinguish good from bad, and self from non-self. Many diseases are associated with lessons poorly learned: autoimmune disease results from the immune system mistaking its own body for pathogens. And we know that colitis is the result of the immune system mistaking commensal bacteria for invaders. Equally dangerous is an under-reactive immune system that doesn’t recognize pathogens as they attack. There is a fine balance here.
How does this process happen though? How is it that our bodies learn that probiotic bacteria should not be attacked as invaders? Researchers at the University of Utah set out to find answers to these questions.[i]
The scientists focused on the thymus gland, which is in the upper chest and makes immune T cells (thus, the “T” cell designation). It also helps educate cells to recognize good/bad, self/nonself. The cells that are flawed and designed to attack self are culled while the good “not self recognizing” cells are sent off into the blood stream to do their jobs. Using mice, they looked at what happens to immune T cells that are specific to one kind of bacteria, when mice are exposed to common gut bacteria. They thought that either the bacteria would be eliminated by the T cells or that the mice would develop anti-inflammatory T cells to protect them from inflammation, as the microbe-specific T-cells attack the commensal bacteria. They were wrong.
So what did happen? “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…” explains the lead researcher.[ii] That is, the thymus created more microbe-specific T cells. How did the bacteria in the gut contact the thymus to tell it to create and send more such immune cells? They actually found bacterial DNA in the thymus gland which demonstrates that the organ is communicating somehow with the gut. Further experimentation showed that bacterial DNA is carried to the thymus by other immune (dendritic) cells, whose job ordinarily is to carry suspicious material to the lymph nodes to be carried out of the body. No one knew that dendritic cells also brought material to the thymus, but in their experiments, that is exactly what the researchers found: “Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.”
As we age, the thymus gland actually becomes less important, but it is particularly critical when we are young. The gland is considered to be a part of the lymph system, and also, a part of the endocrine system. In infants it’s fairly large and continues to grow until puberty, after which it begins to shrink and is replaced by fat.[iii] Thus, it kind of makes perfect sense that the dendritic cells only make the journey from the gut to the gland in very young animals. The lead authors states that, “”What we think is happening is a kind of templating on the immune system…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.” Once the immune system is “trained,” the gland’s main job is done.
How this all relates to some people’s immune system going wild and attacking themselves or their commensal bacteria is still unknown (i.e. does this learning process go on for too long? Not long enough? etc.) – but these scientists plan on further exploring this question to get more answers. The answers may go a long way toward explaining how our immune systems recognized good from bad and why some people develop allergies and autoimmune diseases while others do not – and perhaps give clues as to how to retrain it.
[i] Daniel F. Zegarra-Ruiz, Dasom V. Kim, Kendra Norwood, Myunghoo Kim, Wan-Jung H. Wu, Fatima B. Saldana-Morales, Andrea A. Hill, Shubhabrata Majumdar, Stephanie Orozco, Rickesha Bell, June L. Round, Randy S. Longman, Takeshi Egawa, Matthew L. Bettini, Gretchen E. Diehl. Thymic development of gut-microbiota-specific T cells. Nature, 2021; DOI: 10.1038/s41586-021-03531-1