Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Meakins-Christie Laboratories, McGill University Health Centre, Montreal, Quebec H4A 3J1, Canada.
Immunohorizons. 2020 Apr 24;4(4):217-230. doi: 10.4049/immunohorizons.2000016.
CD8 T cell-mediated immunity is critical for host defense against viruses and requires mitochondria-mediated type I IFN (IFN-I) signaling for optimal protection. Cyclophilin D (CypD) is a mitochondrial matrix protein that modulates the mitochondrial permeability transition pore, but its role in IFN-I signaling and CD8 T cell responses to viral infection has not been previously explored. In this study, we demonstrate that CypD plays a critical extrinsic role in the survival of Ag-specific CD8 T cell following acute viral infection with lymphocytic choriomeningitis virus in mice. CypD deficiency resulted in reduced IFN-I and increased CD8 T cell death, resulting in a reduced antiviral CD8 T cell response. In addition, CypD deficiency was associated with an increase in pathogen burden at an early time-point following infection. Furthermore, our data demonstrate that transfer of wild-type macrophages (expressing CypD) to CypD-deficient mice can partially restore CD8 T cell responses. These results establish that CypD plays an extrinsic role in regulating optimal effector CD8 T cell responses to viral infection. Furthermore, this suggests that, under certain circumstances, inhibition of CypD function may have a detrimental impact on the host's ability to respond to viral infection.
CD8 T 细胞介导的免疫对于宿主抵抗病毒至关重要，需要线粒体介导的 I 型干扰素（IFN-I）信号来实现最佳保护。亲环蛋白 D（CypD）是一种线粒体基质蛋白，可调节线粒体通透性转换孔，但它在 IFN-I 信号转导和 CD8 T 细胞对病毒感染的反应中的作用尚未得到探索。在这项研究中，我们证明 CypD 在小鼠淋巴细胞性脉络丛脑膜炎病毒急性感染后，特异性 Ag CD8 T 细胞的存活中发挥着关键的外在作用。CypD 缺乏导致 IFN-I 减少和 CD8 T 细胞死亡增加，从而导致抗病毒 CD8 T 细胞反应减少。此外，CypD 缺乏与感染后早期病原体负荷增加有关。此外，我们的数据表明，将野生型巨噬细胞（表达 CypD）转移到 CypD 缺陷型小鼠中可以部分恢复 CD8 T 细胞反应。这些结果表明 CypD 在调节对病毒感染的最佳效应 CD8 T 细胞反应中发挥外在作用。此外，这表明在某些情况下，抑制 CypD 功能可能会对宿主抵抗病毒感染的能力产生不利影响。
