Qin Yingyu, Qian Yilin, Liu Shengqiu, Chen Rong
Department of Pathogenic Biology and Immunology, Jiangsu Provincial Key Laboratory of Critical Care Medicine, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, Jiangsu, China.
iScience. 2024 Nov 23;27(12):111462. doi: 10.1016/j.isci.2024.111462. eCollection 2024 Dec 20.
Sepsis, a leading cause of mortality in intensive care units worldwide, lacks effective treatments for advanced-stage sepsis. Therefore, understanding the underlying mechanisms of this disease is crucial. This study reveals that invariant natural killer T (iNKT) cells have an opposing role in the progression of sepsis by suppressing regulatory T (Treg) cell differentiation and function. The activation of iNKT cells by α-Galcer enhances interferon (IFN)-γ production. Blocking antibodies or transferring IFN-γ-deficient iNKT cells demonstrates that iNKT cells inhibit Treg differentiation through IFN-γ production. Additionally, iNKT cell-mediated Treg inhibition prevents secondary infection caused by during the post-septic phase. The transcriptomic analysis of Treg cells further reveals that the suppressive function of Tregs is impaired by iNKT cells. Finally, we demonstrate that iNKT cells inhibit Treg differentiation in an Nr4a1-dependent manner. Our data uncover the dual function of iNKT cells in sepsis progression and provide a potential treatment target for this adverse long-term outcome induced by sepsis.
脓毒症是全球重症监护病房死亡的主要原因，晚期脓毒症缺乏有效的治疗方法。因此，了解这种疾病的潜在机制至关重要。本研究表明，不变自然杀伤T（iNKT）细胞通过抑制调节性T（Treg）细胞的分化和功能，在脓毒症进展中发挥相反作用。α-半乳糖神经酰胺激活iNKT细胞可增强干扰素（IFN）-γ的产生。阻断抗体或转移缺乏IFN-γ的iNKT细胞表明，iNKT细胞通过产生IFN-γ抑制Treg分化。此外，iNKT细胞介导的Treg抑制可预防脓毒症后阶段由[此处原文缺失]引起的继发感染。对Treg细胞的转录组分析进一步表明，iNKT细胞会损害Treg的抑制功能。最后，我们证明iNKT细胞以依赖Nr4a1的方式抑制Treg分化。我们的数据揭示了iNKT细胞在脓毒症进展中的双重作用，并为脓毒症诱导的这种不良长期后果提供了潜在的治疗靶点。
