Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony-stimulating factor (M-CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M-CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon-γ. This depended upon M-CSF-induced myelopoiesis leading to IL15Rα-mediated presentation of IL-15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M-CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G-CSF-mobilized hematopoietic stem and progenitor cells. Together, M-CSF-induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M-CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host-directed therapies.

中文翻译：

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M-CSF 指导骨髓细胞和 NK 细胞分化，以保护造血细胞移植后免受 CMV 侵害

重建自体抗病毒免疫能力的疗法可能代表对免疫抑制个体的重要预防和治疗。造血细胞移植（HCT）后，患者容易感染疱疹病毒，包括巨细胞病毒（CMV）。我们在 HCT 小鼠模型中发现，巨噬细胞集落刺激因子 (M-CSF) 可以促进快速抗病毒活性并防止小鼠 CMV 引起的病毒血症。移植时给予的 M-CSF 刺激了骨髓细胞和自然杀伤 (NK) 细胞的连续分化，最终导致 NK 细胞数量增加、颗粒酶 B 和干扰素 γ 的产生。这取决于 M-CSF 诱导的骨髓细胞生成，导致单核细胞上 IL15Rα 介导的 IL-15 呈递，并通过来自浆细胞样树突状细胞的 I 型干扰素增强。M-CSF 与人类 HCT 相关，可诱导骨髓单核细胞 IL15Rα 表达以及 G-CSF 动员的造血干细胞和祖细胞中功能性 NK 细胞的数量。M-CSF 诱导的骨髓生成共同触发了骨髓细胞和 NK 细胞的整合分化，以保护 HCT 受者免受 CMV 侵害。因此，我们的结果确定了治疗性使用 M-CSF 在免疫功能低下个体中快速重建抗病毒活性的基本原理，这可能为使用宿主导向疗法增强先天抗病毒免疫能力提供一般范例。