美国纽约大学医学院Dan R. Littman研究组发现依赖Prdm16的抗原呈递细胞诱导对肠道抗原的耐受性。2025年4月14日，国际知名学术期刊《自然》发表了这一成果。

该研究团队确定了食物和微生物群特异性pTreg细胞分化所需的APC亚群，并建立了口服耐受性。这些apc的发育和功能需要转录因子Prdm16和RORγt的表达，以及一个独特的Rorc(t)顺式调控元件。基因表达、染色质可及性和表面标记分析表明，pTreg诱导APC起源于髓系，不同于ILC3，与经典树突状细胞（cDC）具有相同的表观遗传谱，并将其命名为Prdm16⁺ RORγt⁺耐受DC （tolDC）。在遗传干扰tolDC后，课题组观察到食物抗原特异性T辅助2 （Th2）细胞的大量增加，而不是pTreg，导致哮喘和食物过敏的无主题模型的耐受性受损。

对人类器官供体新鲜切除的肠系膜淋巴结以及多个人类肠道和扁桃体标本的单细胞分析显示，候选tolDC与PRDM16和RORC共表达，并与小鼠共享广泛的转录组，突出了跨物种的进化保守作用。他们的研究结果表明，更好地了解tolDC如何发展以及它们如何调节T细胞对食物和微生物抗原的反应，可以为开发自身免疫和过敏性疾病以及器官移植耐受的治疗策略提供新的见解。

研究人员表示，胃肠道持续暴露于食物和共生微生物中的外来抗原，具有诱导适应性免疫反应的潜力。外周诱导的T调节性细胞（pTreg）对于减轻对这些药物的炎症反应至关重要^{1- 4}。虽然RORγt⁺抗原呈递细胞（RORγt-APC）被证明可以编程肠道微生物群特异性的pTreg^5-7，但它们的定义仍然不完整，而且负责食物耐受的APC仍然是未知的。

附：英文原文

Title: Prdm16-dependent antigen-presenting cells induce tolerance to gut antigens

Author: Fu, Liuhui, Upadhyay, Rabi, Pokrovskii, Maria, Chen, Francis M., Romero-Meza, Gabriela, Griesemer, Adam, Littman, Dan R.

Issue&Volume: 2025-04-14

Abstract: The gastrointestinal tract is continuously exposed to foreign antigens in food and commensal microbes with potential to induce adaptive immune responses. Peripherally induced T regulatory (pTreg) cells are essential for mitigating inflammatory responses to these agents1–4. While RORγt+ antigen-presenting cells (RORγt-APCs) were shown to program gut microbiota-specific pTreg5–7, their definition remains incomplete, and the APC responsible for food tolerance has remained elusive. Here, we identify an APC subset 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 RORγt, 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 ILC3, and sharing epigenetic profiles with classical dendritic cells (cDC), and designate them Prdm16+ RORγt+ tolerizing DC (tolDC). Upon genetic perturbation of tolDC, we observe a substantial increase in food antigen-specific T helper 2 (Th2) cells in lieu of pTreg, 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 tolDC with co-expression of PRDM16 and RORC and an extensive transcriptome shared with mice, highlighting an evolutionarily conserved role across species. Our findings suggest that a better understanding of how tolDC 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.

DOI: 10.1038/s41586-025-08982-4

Source: https://www.nature.com/articles/s41586-025-08982-4