mTORC2激酶调控记忆性滤泡辅助性T细胞的机制研究

Immunological memory is an important hallmark of the adaptive immune response and provides the hosts with long-term protection from reinfection caused by pathogens. Memory humoral immunity is an important part of immunological memory. B cell response is the core of its function, and memory follicular helper T (TFH) cells play a key role. Memory TFH cells are capable of greatly promoting the rapid differentiation of memory B cells into high affinity plasma cells or germinal center (GC) B cells during secondary response. However, the molecular mechanism of regulating memory TFH cells is still unclear. The mechanism target of rapamycin (mTOR) is a hub connecting the immune microenvironment and intracellular functional state of immune cells. Our previous work showed that mTORC2 plays an essential role in the regulation of memory TFH cell formation and maintenance. Our study intends to further explore the specific role of mTORC2 in the establishment, maintenance and secondary response of memory TFH cells and elucidate the underlying molecular mechanisms by using a mouse model of acute LCMV infection and sophisticated gene-knockout mice, combined with high-throughput sequencing. The research results will lay a solid theoretical basis for vaccine adjuvant development and autoimmune disease treatment, and have great scientific significance and clinical value.

免疫记忆是适应性免疫应答的重要特征，也是保护机体免受病原体再次侵害的长效防护机制。记忆性体液免疫是其重要组成部分，B细胞应答是其发挥作用的核心，而记忆性滤泡辅助性T（TFH）细胞在其中扮演了关键性角色。记忆性TFH细胞能够在二次应答中极大促进记忆性B细胞快速分化为高亲和力浆细胞或生发中心（GC）B细胞的过程。然而目前调控记忆性TFH细胞的分子机制仍不清楚。mTOR是连接免疫微环境和免疫细胞内部功能状态的枢纽。我们的前期工作发现，mTORC2在记忆性TFH细胞生成和维持过程中发挥了重要作用。本研究拟通过小鼠LCMV急性病毒感染模型和精准的基因敲除工具小鼠，结合高通量测序手段，进一步探索mTORC2在TFH细胞免疫记忆建立、维持和二次应答各阶段的具体作用，并从分子水平上阐明其潜在的调控机制。该研究成果将为疫苗佐剂研发和自身免疫病治疗提供重要理论基础，具有重大的科学意义和临床价值。

免疫记忆是适应性免疫应答的重要标志，也是保护机体免受病原体再次侵害的长效防护机制。抗原特异性记忆CD4+ T细胞是免疫记忆的重要组成部分，能够持续存在并快速高效地保护机体免受病原体再感染。然而，记忆CD4+ T细胞库长期维持的机制仍不清楚。在本课题中，我们使用淋巴细胞脉络丛脑膜炎病毒(LCMV)急性感染的小鼠模型，发现丝氨酸/苏氨酸激酶复合物哺乳动物雷帕霉素靶蛋白复合物2 (mTORC2)对病毒特异性记忆CD4+ T细胞的长期维持至关重要。在记忆期干扰mTORC2信号会导致病毒特异性记忆CD4+ T细胞通过一种独特的程序性细胞死亡(RCD)，即铁死亡而大量丢失。机制上，mTORC2失活导致下游AKT和GSK3β激酶无法被磷酸化，从而诱导病毒特异性记忆CD4+ T细胞中异常的线粒体活性氧(ROS)积累，并随后引起脂质过氧化以及铁死亡的发生。此外，这一信号级联的破坏也抑制了谷胱甘肽过氧化物酶4 (GPX4)活性，这是脂质过氧化的主要清除剂。因此，mTORC2-AKT-GSK3β轴作为关键的信号枢纽，通过抑制铁死亡来促进病毒特异性记忆CD4+ T细胞的长期存活。该研究结果将为疫苗佐剂开发和自身免疫性疾病治疗奠定坚实的理论基础，具有重要的科学意义和临床价值。