A newly identified class of immune cells in the gut may hold the key to treating food allergies, according to a study published in Nature by researchers at NYU Langone Health. The cells, called tolerogenic dendritic cells, normally regulate immune responses caused by exposure to food proteins but can cause food allergies if they malfunction.
“Our study shows that RORγt-expressing dendritic cells are key components in the immune regulatory response that prevents food allergies,” said senior author Dan Littman, MD, PhD, a professor in the department of cell biology at NYU Grossman School of Medicine.
“If further experiments prove successful, our findings could lead to innovative ways to treat food allergies,” Littman continued. “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.”
This study builds on Littman’s prior work which showed these cells control immune tolerance to friend bacteria in the gut microbiota that help in food digestion. The Litman Lab, part of NYU Grossman’s Institute for Systems Genetics, focuses on how microbial and immune interactions influence systemic disease. By characterizing the genetic and molecular features of these cells, the new research clarifies their role in both microbial and dietary tolerance.
To identify the tolerogenic dendritic cells (tolDCs) the NYU team employed single-cell RNA sequencing, chromatin profiling, and surface marker analysis. According to the study, “Gene expression, chromatin accessibility, and surface marker analysis establish the pTreg-inducing APCs as myeloid in origin, distinct from ILC3, and sharing epigenetic profiles with classical dendritic cells (cDC), and designate them Prdm16+ RORγt+ tolerizing DC (tolDC).”
In mice lacking these cells, there was a significant drop in peripherally induced regulatory T cells (pTregs), which normally prevent inflammatory responses to food and commensal microbes. Instead, these mice developed elevated numbers of food antigen-specific T helper 2 (Th2) cells, which promote allergic inflammation.
The study also demonstrated that tolDCs require expression of the transcription factors RORγt and Prdm16 as well as a specific regulatory DNA element within the Rorc(t) gene. Disruption of any of these elements impaired the cells’ ability to guide the development of pTreg cells, thereby undermining the body’s tolerance to dietary antigens.
Importantly, tolDC-like cells were identified in human intestinal tissues and lymph nodes. “Single-cell analyses of freshly resected mesenteric lymph nodes from a human organ donor, as well as multiple specimens of human intestine and tonsil, reveal candidate tolDC with co-expression of PRDM16 and RORC and an extensive transcriptome shared with mice, highlighting an evolutionarily conserved role across species,” the researchers wrote.
These findings could contribute to future clinical strategies targeting tolDCs to rebalance immune responses in patients with food allergies or autoimmune disorders. Tolerogenic dendritic cell-based interventions might also be explored to improve outcomes in transplant tolerance and other settings where immune regulation is critical.
“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.
