Our immune system evolved to attack foreign materials entering our body. Food is technically foreign, but it is somehow tolerated by the immune system so that our body can absorb the nutrients. The immune system has built-in tolerance mechanisms that harness itself from responding to benign foreign antigens beneficial to our system, like food. When such tolerance fails, we suffer from an overt immune reaction, such as food allergies, which can be severe enough to be fatal. Despite the increasing incidence and severity of food allergies, the details on how immune tolerance to dietary antigens is normally established remain largely unknown. Scientists from the Academy of Immunology and Microbiology (AIM) within IBS in South Korea have recently uncovered one of the key mechanisms in the small intestine that triggers this process.

A key mechanism used by our body to induce immune tolerance is by induction of regulatory T (Treg) cells, a subset of white blood cell that orders other T cells to stand down. In the gut, a special subset of Treg cells, called peripheral Treg (pTreg) cells, exists in both the small and large intestine. Previous research showed that pTreg cells are created in the large intestine in response to the normal commensal intestinal bacteria, which play a vital symbiotic role in our health. pTreg cells were also believed to exist in the small intestine to inform the immune system on which food antigens can enter our body. The IBS research team has now discovered that normal diet does indeed induce the creation of the pTreg cells in the small intestine.

Experiments with Mice

▲ AF_GF_SPF MOUSE

To determine whether normal food prompts mucosal immunity in the intestines, the research team generated a special type of mice, dubbed “antigen-free” mice that were not used in research since the 1980’s. Through a painstaking process, these antigen-free mice were generated from germ-free parents who are completely devoid of any microorganisms. Like their parents, antigen-free mice are also germ free, but they are also fed a meticulously assembled, ultra-refined “elemental” diet comprised of basic building blocks of life that keeps them alive and healthy, but is free of antigens (macromolecules) that can activate the immune system.

In essence, antigen-free mice were generated in order to test whether typical food antigens actually contributed to the development of pTreg cells in the small intestine. The result was that like germ-free mice, the antigen-free mice were depleted of pTreg cells in their colon, but what was new and exciting was that they also lacked pTreg cells in their small intestines. Hence, it became clear that normal dietary antigens were responsible for signaling pTreg cells to be generated at this site.

Dietary Evolution: Liquid to Solids

To determine how early in ontogeny pTreg cells develop the IBS researchers compared the effect of milk vs. a solid food diet in pre and post-weaned mice. Neonatal mice on milk possessed only a few pTreg cells in the small intestine. Later, when these mice were weaned onto a solid food diet, large numbers of pTreg cells in the small intestine emerged rapidly within a few weeks. However, when neonatal mice were weaned onto an antigen-free elemental diet or a diet free of proteins, but only their amino acid building blocks, they didn’t develop pTreg cells in the small intestine. From this they concluded that the majority of pTreg cells in the small intestine develop in response to antigens derived from proteins in a solid food diet.

These findings beg the question: Why don’t all neonatal mice that haven’t had a chance to eat solid food (and develop pTreg cells) immediately get food allergies when weaning off of milk? According to researcher Kwang Soon Kim, “In early life, the intestinal environment is more skewed to generate a tolerogenic response, presumably helped by certain tolerance-inducing components in the milk, and from the rapid generation of pTreg cells upon introduction of solid food.” Hence, mother’s milk and newly generated pTreg cells appear to work together to prevent food allergies when toddlers begin to enjoy rice and other solid food. This idea is also supported by the researchers’ finding that when neonatal mice were allowed to grow into adults without pTreg cells, i.e., without exposure to solid food, they` become much more susceptible to experimentally induced food allergy.

Forward Thinking

A recent study from the UK called LEAP (Learning Early About Peanut allergy) set out to prove that “regular eating of peanut-containing products, when started during infancy, will elicit a protective immune response instead of an allergic immune reaction”. The results were astounding; 17% of the children who avoided peanut-containing products developed allergies by the age of 5. Remarkably, only 3% of the children who ate peanut-containing products developed allergies by the same age. The trial, taken as a microcosm, confirms AIM’s director Surh’s assertions, “our data could explain why children suffer from a higher incidence of food allergy than adults and why childhood allergy spontaneously dissipates with time.” With the results from both Korea and the UK the presence of both diet and microbe-induced populations of pTreg cells may be required for the development of complete tolerance to food antigens.

Food allergies are on the rise, affecting 1 in every 13 children in America, so it is becoming critical to understand how to control and eliminate allergic responses. While this study didn’t focus directly on food hypersensitivity treatments, the antigen-free mice provided a better understanding of the processes involved in food allergies. This work may be a small part of something larger as Professor Surh said, “I believe that dietary antigens might also affect autoimmune diseases in other organs”. This work brings us one step closer to understanding how the body’s immune response works and what we can do to control it.

Notes for editors

- References
Kwang Soon Kim, Sung-Wook Hong, Daehee Han, Jaeu Yi, Jisun Jung, Bo-Gie Yang, Jun Young Lee, Minji Lee and Charles D. Surh; Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine, Science DOI: XX.XXX

- Media Contact
For further information or to request media assistance, please contact: Mr. Shi Bo Shim, Head of Department of Communications, Institute for Basic Science (+82-42-878-8189; sibo@ibs.re.kr) or Ms. Dahee Carol Kim, Department of Communications, Institute for Basic Science (+82-42-878-8133; clitie620@ibs.re.kr)

- About the Institute for Basic Science (IBS)
IBS was founded in 2011 by the government of the Republic of Korea with the sole purpose of driving forward the development of basic science in Korea It comprises a total of 50 research centers in all fields of basic science, including mathematics, physics, chemistry, life science, earth science and interdisciplinary science. IBS has launched 26 research centers as of January 2016. There are 8 physics, 1 mathematics, 6 chemistry, 8 life science, and 3 interdisciplinary research centers.