If you are allergic to peanuts, milk products, or strawberries, you usually blame your immune system for this unfortunate reaction. But when people enjoy a varied diet without any troublesome reaction, they generally don’t realize that this is thanks to their immune system.
Our ability to ingest chicken, meat, or tomatoes, for example – which constitute material foreign to the body and could have been a hostile invader – is due to the immune mechanism known as oral tolerance. Though this tolerance is vital for our survival, how it works had remained puzzling despite years of research.
Now, a new study entitled “A coordinated cellular network regulates tolerance to food,” published in the prestigious journal Nature by Dr. Ranit Kedmi and her team at the Department of Systems Immunology at the Weizmann Institute of Science in Rehovot, has resolved a long-standing paradox surrounding oral tolerance and revealed the cellular network that is responsible.
Their findings could help researchers understand this network’s malfunctions that underlie food allergies, sensitivities, and disorders such as celiac disease (a bad reaction to gluten in foods containing wheat, spelt, barley, and rye).
Tolerance to food begins to develop in the womb as the fetus’s immune system is exposed to substances derived from food consumed by the mother. It continues to mature while she nurses the baby and as the child begins to eat solid food, as well as through interactions with beneficial gut bacteria that produce their own potential allergens that the immune system must learn to ignore.
Division of labor in the immune system
For years, tolerance to food was thought to be orchestrated by immune cells called dendritic cells (DC).
They were discovered by Prof. Ralph Steinman, a Canadian-born Jewish physician and medical researcher at Rockefeller University in New York City. For his research on the leading causes of the immune system’s attacks, he was posthumously awarded the 2011 Nobel Prize in Physiology or Medicine. When announcing the prize, the Nobel committee was unaware that Steinman had died from pancreatic cancer three days earlier.
In infection, DCs chop up microbes and present their bits and pieces to other cells, triggering an assault by the immune system. The prevailing view of oral tolerance was that, after checking out digested food, DCs could instead decide to keep that attack at bay, instructing the immune cells to stand down and suppress any action.Yet, strangely, when researchers eliminated the suspected subset of DCs in animal models, oral tolerance still developed.
Kedmi thought that the answer must be sought in a type of cell she had discovered during her postdoctoral studies: ROR-gamma-t cells, whose exact lineage is still unknown. This hunch proved true.
In their new study, Kedmi’s team, led by doctoral student Anna Rudnitsky, showed that ROR-gamma-t, rather than conventional dendritic cells, set off the tolerance mechanism. When Rudnitsky eliminated the ability of these particular cells to introduce food particles to the immune system in mice, the animals rapidly developed food allergies.
“Apparently, there is much more division of labor in the immune system than previously appreciated,” Kedmi told The Jerusalem Post in an interview. “We want to understand food sensitivities in general. The reason why babies are exposed to peanut products like Bamba as a positive experience early in their lives is that it causes oral tolerance. If they are exposed to infection, which is a negative experience, it could be harmful.”
She added, “It’s not that dendritic cells always decide whether or not to attack foreign substances. Instead, completely different players – specific, rare cells – are dedicated to launching a mechanism that makes sure we can consume food safely.”
They next aimed to fully decipher the oral tolerance mechanism. By selectively manipulating genes and eliminating different cell types in mice and then using advanced genetic tools and microscopy to monitor cellular responses to food, the researchers identified a coordinated network of four cell types crucial for preventing immune reactions to food.
This network is initiated by ROR-gamma-t cells, and their signals are relayed through two other cell types to ultimately suppress the fourth, the immune system’s militant CD8 cells, which normally have the job of killing infected cells or triggering inflammation against perceived threats.
These discoveries, particularly of the last link in the network, raised further intriguing questions for Kedmi. What would happen if the immune system encountered microbial proteins that are similar to food ingredients? How could it effectively fight microbial infection after suppressing the CD8 response to these ingredients? And, if oral tolerance suppresses this immune response, why haven’t microbes evolved to disguise themselves as food to evade CD8’s killing power?
To address these questions, the researchers tested whether mice could develop immunity to a microbe that expresses a protein already identified by the mouse immune system as food. They revealed a remarkable reaction: Faced with a threat, the mice’s immune systems temporarily suspended the tolerance program, deploying CD8 cells to combat the infection. Only after the infection cleared did the cellular network enable the tolerance program to resume.
Using the analogy of two peaceful neighboring countries, Kedmi said that “if an aggressor suddenly fires across the border, that person will be swiftly neutralized by the other side’s forces, peace accords notwithstanding. The immune system operates on a similar principle. In the face of infection, it prioritizes fighting the disease-causing microbe, temporarily setting aside tolerance mechanisms.”
Thus, the team has discovered a sophisticated, dynamic cellular network that allows the immune system to prevent inflammatory responses to food while simultaneously staying on guard against infection. This discovery opens promising new avenues for research into malfunctions in the oral tolerance mechanism that lead to allergies and diseases.
It may explain how the final stage of the tolerance mechanism, the suppression of the CD8 cells, fails in celiac disease, causing the CD8s to mistakenly attack the intestinal lining in response to gluten. A detailed understanding of the specific points of failure within the oral tolerance network in all types of food allergies and sensitivities could pave the way for improved treatments, the study stated.
