Prdm16-dependent antigen-presenting cells induce tolerance to intestinal antigens

Area of Science:

• Immunology
• Cell Biology
• Gastroenterology

Background:

• The gastrointestinal tract constantly encounters food antigens and microbes, necessitating immune regulation to prevent inflammation.
• Peripherally induced T regulatory (pTreg) cells are critical for immune tolerance, but the specific antigen-presenting cells (APCs) responsible for food tolerance remain largely undefined.
• RORγt+ APCs are known to induce gut microbiota-specific pTreg cells, yet their full role and identity in oral tolerance are incomplete.

Purpose of the Study:

• To identify and characterize the specific APC subset responsible for inducing regulatory T cell responses to food antigens.
• To elucidate the developmental requirements and functional role of these APCs in establishing oral tolerance.
• To investigate the evolutionary conservation of these regulatory mechanisms in humans.

Main Methods:

• Identification of a novel RORγt+ APC subset, termed tolerogenic dendritic cells (tDCs), using gene expression, chromatin accessibility, and surface marker analysis.
• Genetic perturbation studies in mouse models to assess the impact of tDC deficiency on T cell differentiation and oral tolerance.
• Single-cell transcriptomic analysis of human tissues (mesenteric lymph nodes, intestine, tonsil) to identify conserved tDC populations.

Main Results:

• A distinct subset of RORγt+ APCs, designated tDCs, was identified as essential for differentiating both food- and microbiota-specific pTreg cells, thereby establishing oral tolerance.
• tDC development and function depend on the transcription factors Prdm16 and RORγt, and a unique Rorc(t) cis-regulatory element.
• Perturbation of tDCs led to increased T helper 2 (Th2) cells instead of pTregs, resulting in impaired tolerance in mouse models of asthma and food allergy.
• Human tissues revealed candidate tDCs expressing PRDM16 and RORC, sharing transcriptional profiles with mouse tDCs, indicating an evolutionarily conserved function.

Conclusions:

• Tolerogenic dendritic cells (tDCs) are a critical myeloid APC subset required for inducing regulatory T cell responses to food and microbial antigens, essential for oral tolerance.
• The development and function of tDCs are regulated by specific transcription factors (Prdm16, RORγt) and cis-regulatory elements.
• Understanding tDC biology offers potential therapeutic avenues for managing allergic and autoimmune diseases, as well as improving organ transplant tolerance.