PRDM16-dependent antigen-presenting cells induce tolerance to gut antigens

Area of Science:

• Immunology
• Gastroenterology

Background:

• The gastrointestinal tract faces constant exposure to food and microbial antigens, necessitating robust immune regulation.
• Peripherally induced T regulatory (pT_reg) cells are vital for controlling inflammatory responses to these antigens.
• While RORγt+ antigen-presenting cells (APCs) are known to induce microbiota-specific pT_reg cells, the APC responsible for food tolerance remained unidentified.

Purpose of the Study:

• To identify the specific APC subset responsible for inducing both food- and microbiota-specific pT_reg cells.
• To elucidate the molecular mechanisms governing the development and function of these APCs.
• To investigate the role of these APCs in establishing oral tolerance and their potential implications in allergic and autoimmune diseases.

Main Methods:

• Gene expression analysis, chromatin accessibility assays, and surface marker profiling to define APC characteristics.
• Genetic perturbation studies in mouse models to assess the functional impact of APCs on immune responses.
• Single-cell transcriptomic analysis of human tissues (mesenteric lymph nodes, intestine, tonsil) to identify conserved cell populations.

Main Results:

• Identification of a novel APC subset, termed PRDM16+RORγt+ tolerizing dendritic cells (tolDCs), essential for pT_reg cell differentiation.
• Demonstration that tolDC development requires PRDM16 and RORγt expression.
• Perturbation of tolDCs led to increased T helper 2 cells instead of pT_reg cells, compromising oral tolerance and exacerbating allergy models.
• Identification of analogous tolDC populations in human tissues, suggesting evolutionary conservation.

Conclusions:

• PRDM16+RORγt+ tolDCs are critical regulators of oral tolerance by inducing pT_reg cells specific to food and microbial antigens.
• Dysfunction of tolDCs can lead to inflammatory conditions like food allergy and asthma.
• These findings offer new therapeutic avenues for managing autoimmune and allergic diseases, and potentially enhancing transplant tolerance.