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The immune system plays a critical role in defending the body from pathogens like viruses. However, it must also differentiate between harmful invaders and benign substances to prevent allergic reactions. A key aspect of this differentiation involves immune cells that typically ignore molecules present on healthy cells or non-threatening external elements, such as food. The mechanisms behind this tolerance have long been a subject of investigation.
Recent research spearheaded by scientists at NYU Langone Health has uncovered important insights into how the immune system regulates responses to food proteins. This study highlights a specialized group of cells located in the intestines, known as “tolerogenic dendritic cells.” These cells help manage the immune reactions provoked by food, allowing these substances to pass through the digestive system without inciting an immune response, barring any malfunctions that could lead to allergies.
The study identified that tolerogenic dendritic cells rely on specific proteins, namely Retinoic Acid-Related Orphan Receptor-gamma-t (RORγt) and PR domain-containing 16 (Prdm16), to maintain control over the immune responses triggered by food proteins. In experiments where these cells were not functioning properly, mice displayed a heightened susceptibility to developing food allergies and asthma.
Earlier research had indicated that these dendritic cells also play a crucial role in fostering tolerance towards beneficial gut bacteria, which are instrumental in digestion and the regulation of various bodily functions. However, the scope of their functionality was not fully understood until now.
According to Dr. Dan Littman, the senior author of the study and a prominent molecular immunologist at NYU Grossman School of Medicine, “Our study demonstrates that dendritic cells expressing RORγt are essential in the immune response that prevents food allergies.” He further emphasized the significance of these cells, noting their role in maintaining harmony with the extensive microbiome within our bodies and their potential to combat autoimmune disorders like Crohn’s disease.
Through genetic and protein expression analysis, researchers classified these cells as a variety of dendritic cell within the immune system. Traditionally, dendritic cells are tasked with presenting antigens, small fragments of biological entities, to T cells, which then activate an immune response during subsequent encounters. However, the study revealed a distinct response when tolerogenic dendritic cells present food or microbial antigens to T cells, prompting the latter to become regulatory and anti-inflammatory. Instead of instigating an attack, these T cells work to suppress inflammation, particularly in relation to food and microbial antigens.
Published on April 14 in the journal Nature, the study demonstrated that mice lacking tolerogenic dendritic cells experienced a reduction in regulatory T cells, which are crucial for controlling inflammation linked to food and microbial antigens. These mice also showed an increase in pro-inflammatory T cells that are associated with allergies and inflammatory responses.
A significant aspect of the research involved the identification of human counterparts to these tolerogenic dendritic cells by analyzing intestinal tissue and public sequencing databases. While it remains uncertain how prevalent these cells are in humans or their roles in immune tolerance beyond the intestines, the comprehensive identification paves the way for future inquiries into these important questions.
Dr. Littman suggested that successful further research could ultimately lead to new therapeutic avenues for managing food allergies. For instance, in cases of peanut allergy, leveraging tolerogenic dendritic cells might enhance the presence of regulatory T cells and mitigate allergic reactions to peanut proteins.
Future investigations will focus on the origins and developmental pathways of tolerogenic dendritic cells, including the signaling mechanisms required for their functionality.
This research received funding from a range of National Institutes of Health grants, underscoring the collaborative effort behind the findings. In addition to Dr. Littman, the study involved contributions from co-first authors Liuhui Fu, Rabi Upadhyay, and Maria Pokrovskii, along with co-authors Francis Chen, Gabriela Romero-Meza, and Adam Griesemer.
Dr. Littman also has affiliations with several biotechnology companies and advisory positions, which are managed under NYU Langone Health’s policies to avoid conflicts of interest.
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