The immune system must be able to quickly attack invaders like viruses, while also ignoring harmless stimuli, or allergies can result. Immune cells are known to ignore or "tolerate" molecules found on the body's own healthy cells, for instance, as well as nonthreatening substances from outside the body like food. How the system achieves the latter has been unclear.
Now, a new study led by researchers at NYU Langone Health has revealed that a special group of cells in the intestines tamp down the immune responses caused by exposure to food proteins. Called "tolerogenic dendritic cells," these cells enable food to pass through the body without triggering an immune reaction, unless they malfunction to cause allergies.
The cells were also found to require the proteins Retinoic Acid-Related Orphan Receptor-gamma-t (RORγt) and PR domain-containing 16 (Prdm16) to effectively protect tolerated proteins from the inrush of immune cells and proteins meant to destroy foreign cells (inflammation). Without properly functioning tolerogenic dendritic cells, mice in the study were more prone to develop food allergies and asthma.
Previous work by the team had revealed that these same cells control immune tolerance to friendly gut bacteria, which help humans to digest food and to control functions of multiple organ systems. But at the time, the researchers knew little about their identity or whether these cells controlled tolerance to anything else.
"Our study shows that RORγt-expressing dendritic cells are key components in the immune regulatory response that prevents food allergies," said study senior author Dan Littman, MD, PhD, the Helen L. and Martin S. Kimmel Professor of Molecular Immunology in the Department of Pathology, and a professor in the Department of Cell Biology, at NYU Grossman School of Medicine.
"This discovery adds evidence to our earlier work showing that these cells also keep the peace with the vast microbiome, the mix of microbes that inhabits our body, and may be important for preventing autoimmune conditions like Crohn's disease," said Littman, who is also a Howard Hughes Medical Institute Investigator.
By analyzing the genes and proteins these cells express and comparing them to well-understood cell types, the researchers concluded that they are a type of immune cell called a dendritic cell. Typically, dendritic cells present tiny fragments of biological material (known as antigens) for notice by other immune cells called T cells. This programs the T cell to launch an immune attack the next time it encounters the antigen.
But the researchers showed that when the tolerogenic dendritic cells present antigens from food or friendly microbes to T cells, the T cells become anti-inflammatory, or "regulatory." This means that the next time that the T cell encounters the antigen, instead of attacking, it will suppress nearby inflammation.
Publishing in the journal Nature online April 14, the study showed that in mice without tolerogenic dendritic cells, there were fewer regulatory T cells ready to prevent inflammation caused by food or microbial antigens. Those mice also had more inflammatory T cells that caused allergies and inflammation when exposed to those antigens.
Another key finding from the paper was that by analyzing human intestinal tissue and public sequencing datasets, the researchers found the human equivalents of tolerogenic dendritic cells. Littman says it is not yet clear how abundant these cells are inside the human body or whether they are involved in other forms of immune tolerance outside the intestines. But those questions should be easier to answer because of how comprehensively the researchers identified the cells in the new study.
"If further experiments prove successful, our findings could lead to innovative ways to treat food allergies," said Littman. "For example, if someone has a peanut allergy, perhaps we can use tolerogenic dendritic cells to help create more regulatory T cells to suppress an allergic response to peanut molecules."
Moving forward, Littman said the researchers also want to more deeply understand how and where tolerogenic dendritic cells develop in the body and what kinds of signals they need to receive to perform their function.
Funding support for this study was provided by National Institutes of Health grants P30CA016087, R01AI158687, T32AL100853, F32AI181496, and K08CA283272.
In addition to Littman, other NYU Langone researchers involved in this study include co-first authors Liuhui Fu, Rabi Upadhyay, Maria Pokrovskii; and co-authors Francis Chen, Gabriela Romero-Meza, Adam Griesemer.
Littman is a co-founder of Vendanta Biosciences and ImmunAI, and serves on the advisory boards of IMIDomics, Sonoma Biotherapeutics, NILO Therapeutics, and Evommune, and on the board of directors of Pfizer Inc.
None of these groups were involved in the current study. The terms and conditions of these relationships are being managed in accordance with the policies and procedures of NYU Langone Health.
