Study unveils how gut immune cells differentiate between nutrients and harmful pathogens, providing insights into the causes of food allergies and intestinal disorders.
Every time we eat, our gut’s immune system faces a crucial choice. It must protect us from harmful pathogens while recognizing harmless food and beneficial bacteria. Understanding how the gut can differentiate between these elements has been a longstanding mystery for researchers.
Recent research has identified particular cell types in the gut that interact with T cells, guiding them to either tolerate, attack, or disregard substances. The study, published in Science, enhances our understanding of how the gut’s immune system maintains balance and could reveal the underlying mechanisms related to food allergies and digestive diseases.
“The main question is, how do we manage to eat food without harm?” says Maria C.C. Canesso, the lead author and postdoctoral fellow in the labs of Daniel Mucida and Gabriel D. Victora. “Why does our body generally accept food, and what happens when food allergies develop?”
Making Decisions in the Gut
The intestinal immune system operates through complex mechanisms. Food tolerance starts when antigen-presenting cells (APCs) signal T cells to relax. This process generates pTregs, a unique type of T cell that helps moderate the immune response to food particles, initiating a chain of activity involving other immune cells that support this message. However, pinpointing the specific APCs responsible remains challenging, complicating our understanding of how the body achieves food tolerance and reacts to pathogens.
“There are numerous types of antigen-presenting cells,” Canesso mentions. “Identifying which ones perform specific roles has been a persistent technical hurdle.”
Canesso started investigating this challenge as a PhD candidate in the Mucida lab, focusing on how the intestine balances its defensive actions with tolerance. During her postdoc, she collaborated with the Victora lab, which developed a technology named LIPSTIC, designed to help researchers catalog interactions between cells, especially immune cells.
“The advancements from the Victora lab allowed us to explore immune cell interactions that previous approaches couldn’t achieve,” states Mucida, head of the Laboratory of Mucosal Immunology.
After fine-tuning LIPSTIC for this research, Canesso and her team successfully identified the APCs that facilitate tolerance—primarily involving two types: cDC1s and Rorγt+ APCs. These cells capture dietary antigens from the food and present them to T cells, resulting in pTregs that promote food tolerance.
“When we initially developed LIPSTIC, our goal was to measure the interactions between B and T cells related to vaccine-induced antibody responses,” says Victora, head of the Laboratory of Lymphocyte Dynamics. “Maria adapted this technology for a completely different context, which is commendable.”
They also discovered how intestinal infections can disrupt this balance. Research on mice showed that the parasitic worm Strongyloides venezuelensis shifts the focus from tolerance-promoting APCs to those that incite inflammation. Mice exposed to this worm showed decreased tolerance to a dietary protein during their initial encounter and exhibited allergy symptoms upon re-exposure.
Finally, the research team outlined the molecular signals that drive these immune changes, identifying critical cytokines and pathways affecting APC function and immune response regulation. For instance, infections triggered a rise in pro-inflammatory cytokines like IL-6 and IL-12, which are known to push APC activity toward inflammatory responses. This inflammation disrupts the immune system’s ability to maintain tolerance. “The worm infection causes an increase in non-tolerogenic APCs that manage the infection, outnumbering those that support tolerance,” Canesso explains.
Linking Food to Allergies
These findings enhance our understanding of how the immune system achieves food tolerance while also revealing the specific immune processes that can become dysfunctional during parasitic infections. “It’s crucial to clarify that our research does not imply that worm infections cause food allergies,” Mucida emphasizes, head of the Laboratory of Mucosal Immunology. “Instead, they weaken tolerance mechanisms as the immune system prioritizes tackling the worms.”
Although these results do not directly address food allergies, they pave the way for further research into food intolerances. “If food allergies stem from dysfunctional intestinal APCs that fail to induce tolerance while responding to infections, there may be potential to adjust those APCs to prevent food allergies in the future,” Canesso suggests.
Looking ahead, Canesso intends to focus on the early stages of life, investigating how interactions between mothers and newborns may impact food intolerance. “Most allergies arise early in life,” she states. “I aim to study how breast milk and maternal exposure to dietary antigens can shape a child’s immune system and influence their likelihood of developing food allergies.”
