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

• 成果类型: Article
• 署名作者: Fu, Liuhui; Upadhyay, Rabi; Pokrovskii, Maria; Chen, Francis M.; Romero-Meza, Gabriela; Griesemer, Adam; Littman, Dan R.
• 署名单位: New York University; NYU Langone Medical Center; Howard Hughes Medical Institute; NYU Langone Medical Center
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1693
• DOI: 10.1038/s41586-025-08982-4
• 发表日期: 2025-06-19
• 关键词: regulatory t-cells; ror-gamma-t; nuclear receptor; dendritic cells; intestinal inflammation; oral tolerance; food allergy; mice; differentiation; alpha

摘要

The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microorganisms with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1, 2, 3-4. Although ROR gamma t+ antigen-presenting cells (APCs) have been shown to programme gut microbiota-specific pTreg cells5, 6-7, their definition remains incomplete, and the APC responsible for food tolerance has remained unknown. Here we identify an APC subset that is required for differentiation of both food- and microbiota-specific pTreg cells and for establishment of oral tolerance. Development and function of these APCs require expression of the transcription factors PRDM16 and ROR gamma t, as well as a unique Rorc(t)cis-regulatory element. Gene expression, chromatin accessibility, and surface marker analysis establish the pTreg-inducing APCs as myeloid in origin, distinct from type 3 innate lymphoid cells, and sharing epigenetic profiles with classical dendritic cells, and designate them PRDM16+ROR gamma t+ tolerizing dendritic cells (tolDCs). Upon genetic perturbation of tolDCs, we observe a substantial increase in food antigen-specific T helper 2 cells in lieu of pTreg cells, leading to compromised tolerance in mouse models of asthma and food allergy. 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 tolDCs with co-expression of PRDM16 and RORC and an extensive transcriptome shared with tolDCs from mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tolDCs develop and how they regulate T cell responses to food and microbial antigens could offer new insights into developing therapeutic strategies for autoimmune and allergic diseases as well as organ transplant tolerance.