Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
Sci Immunol. 2022 Mar 25;7(69):eabn8041. doi: 10.1126/sciimmunol.abn8041.
Targeting the potent immunosuppressive properties of FOXP3 regulatory T cells (T) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling T homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of T homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in T led to accumulation of effector T resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8-deficient lymphoid and tissue T, which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human T have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in T that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.
靶向 FOXP3 调节性 T 细胞（T 细胞）的强效免疫抑制特性，对于治疗自身免疫和炎症性疾病具有巨大的治疗潜力。然而，控制 T 细胞稳态的分子机制，特别是在炎症期间，仍然不清楚。我们报告说，caspase-8 以一种特定于上下文的方式，成为 T 细胞稳态的核心调节剂，在免疫反应中具有决定性作用。在小鼠遗传模型中，靶向 T 细胞中的 caspase-8 会导致效应 T 细胞积累，使其对凋亡细胞死亡产生抗性。相反，炎症会诱导 caspase-8 缺陷的淋巴和组织 T 细胞发生依赖 MLKL 的坏死性凋亡，从而增强对多种慢性感染的免疫力，促进清除病毒或寄生虫病原体。然而，更好的免疫会增加在压倒性感染中发生致命炎症的风险。使用一种临床阶段的化合物抑制 caspase-8，揭示了与传统 T 细胞相比，人类 T 细胞对坏死性凋亡具有更高的敏感性。这些发现揭示了 T 细胞中的一个基本机制，该机制可能成为治疗的靶点，以调节免疫耐受与反应之间的平衡，从而获得治疗益处。
