PRDM16-Dependent Antigen-Presenting Cells Induce Tolerance to Gut Antigens

A subset of antigen-presenting cells (APCs) of myeloid origin that require PRDM16 and RORγt regulates T cell function to enable immune tolerance of food and commensal gut microorganisms. Therefore, this study investigated the role of RORγt-APCs in the induction of tolerance to oral antigen. To identify cell-type-specific regulatory sequences, bulk assay for transposase-accessible chromatin with sequencing analyses was conducted in several RORγt-expressing cell types. Then, single-cell RNA sequencing (scRNA-seq) was performed on MHCII-expressing innate immune system cells from mesenteric lymph nodes (mLNs) of control and mutant mice to better define the RORγt-dependent APCs required for intestinal peripherally induced T regulatory (pTreg) cell differentiation. In addition, scRNA-seq was performed on HLA-DR-enriched cells from freshly isolated mLNs of a 22-year-old trauma patient with no known history of atopy or chronic disease to determine whether the tolerizing dendritic cells identified in mice are also present in humans. The results indicate that RORγt drives the development of a unique PRDM16-expressing dendritic cell-like subset, and both RORγt and PRDM16 are required for these APCs to induce pTreg cells that regulate inflammatory responses to food and microbiota antigens.