Versiti Blood Research Institute, 8727 West Watertown Plank Rd., Milwaukee, WI 53213, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 West Watertown Plank Rd., Milwaukee, WI 53226, USA.
Versiti Blood Research Institute, 8727 West Watertown Plank Rd., Milwaukee, WI 53213, USA; Department of Microbial Infection and Immunity, The Ohio State University College of Medicine, 370 W. 9(th) Ave., Columbus, OH 43210, USA; Pelotonia Institute for Immuno-Oncology, The James Comprehensive Cancer Center, The Ohio State University, 460 W. 10(th) Ave., Columbus, OH 43210, USA.
Cell Rep. 2021 May 25;35(8):109160. doi: 10.1016/j.celrep.2021.109160.
The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. We perform single-cell RNA sequencing of myeloid cells during acute and chronic lymphocytic choriomeningitis virus (LCMV) infection to address this question. Our analysis identifies a cluster of suppressive neutrophils that is enriched in chronic infection. Furthermore, suppressive neutrophils highly express the gene encoding Proviral integration site for Moloney murine leukemia virus-1 (PIM1), a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminishes suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid-derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils leads to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity is required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function causes increased suppressive neutrophil apoptosis.
针对慢性病毒感染的免疫反应是经过精心调整的，以平衡病毒控制和免疫病理学。然而，髓样细胞在塑造慢性病毒感染反应中的作用还知之甚少。我们在急性和慢性淋巴细胞脉络丛脑膜炎病毒 (LCMV) 感染期间对髓样细胞进行单细胞 RNA 测序，以解决这个问题。我们的分析确定了一群在慢性感染中富集的抑制性中性粒细胞。此外，抑制性中性粒细胞高度表达编码 Moloney 鼠白血病病毒-1 (PIM1) 前病毒整合位点的基因，PIM1 是一种已知能促进线粒体健康和细胞存活的激酶。PIM1 的药理学抑制选择性地减少抑制性中性粒细胞介导的免疫抑制，而不影响单核细胞来源的髓样抑制细胞 (M-MDSC) 的功能。抑制性中性粒细胞积累减少导致 CD8 T 细胞功能和病毒控制增加。在机制上，PIM 激酶活性对于维持抑制性中性粒细胞中的融合线粒体网络是必需的，但对于 M-MDSC 则不是必需的，而 PIM 激酶功能的丧失导致抑制性中性粒细胞凋亡增加。
