Li Peng, Zhang Yime, Shen Yang, Zhao Xingyu, Mu Rong, Zhong Chao
Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Researches on Major Immunology-Related Diseases, Peking University, Beijing, China; Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing, China.
Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Medicine Innovation Center for Fundamental Researches on Major Immunology-Related Diseases, Peking University, Beijing, China; Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing, China.
Cell Rep. 2025 Jun 24;44(6):115793. doi: 10.1016/j.celrep.2025.115793. Epub 2025 Jun 5.
RORγt inhibition shows potential for treating T helper 17 (Th17) cell-related inflammatory disorders. However, there is a lack of a comprehensive understanding of its influence on the immune system. RORγt also serves as the master regulator of type 3 innate lymphoid cells (ILC3s). Although previous studies indicated that it might not be essential for ILC3 activation, our single-cell RNA sequencing analysis reveals its fundamental participation. By utilizing an Il22Rosa26Rorc (interleukin [IL]-22-fate mapping [FM]) mouse model, we discovered that genetic deletion of Rorc does not completely eliminate ILC3s. Only the lymphoid tissue inducer (LTi) subset experiences a reduction. Additionally, the "ex-ILC3s" following Rorc deletion still preserve ILC3 characteristics and produce sufficient IL-22 to maintain gut health and prevent pathogen invasion. Nevertheless, RORγt is found to be crucial for heparin-binding epidermal growth factor (HB-EGF) production in activated ILC3s, which is of great significance in alleviating colitis. Thus, our findings clarify the role of RORγt in ILC3s, thereby providing insights for the clinical evaluation of RORγt inhibition.
RORγt抑制在治疗与辅助性T细胞17（Th17）细胞相关的炎症性疾病方面显示出潜力。然而，目前对其对免疫系统的影响缺乏全面了解。RORγt也是3型固有淋巴细胞（ILC3s）的主要调节因子。尽管先前的研究表明它可能对ILC3激活并非必不可少，但我们的单细胞RNA测序分析揭示了它的重要参与。通过利用Il22Rosa26Rorc（白细胞介素[IL]-22命运图谱[FM]）小鼠模型，我们发现Rorc的基因缺失并未完全消除ILC3s。只有淋巴组织诱导细胞（LTi）亚群有所减少。此外，Rorc缺失后的“前ILC3s”仍保留ILC3特征，并产生足够的IL-22以维持肠道健康并防止病原体入侵。然而，发现RORγt对活化的ILC3s中肝素结合表皮生长因子（HB-EGF）的产生至关重要，这在减轻结肠炎方面具有重要意义。因此，我们的研究结果阐明了RORγt在ILC3s中的作用，从而为RORγt抑制的临床评估提供了见解。
