Gene expression profile at single cell level of monocytes (MOs) and T cells from the lungs and from broncho-alveolar lavage fluids (BALF) from Mock and MuHV-4 infected WT and CCR2 KO mice.

Gammaherpesviruses (?HVs) have co-evolved with their hosts over millions of years, leading to remarkably high infection prevalence and establishment of symbiotic relationship. Therefore, the lifelong persistence of ?HVs appear to broadly shape host immunity. Here, we show that pulmonary infection with Murid herpesvirus 4 (MuHV-4), a mouse ?HV, drives the recruitment in the airways of Ly6Chi monocytes (MOs) that control the host immune response. Indeed, the absence of those MOs elicits a severe virus-induced immunopathology associated with the systemic release of inflammatory mediators. Mechanistically, MuHV-4 imprinted MOs recruit CD4 T cells in the airways and trigger immunosuppressive signalling pathways through the PDL1/PD-1 axis, thereby dampening the deleterious activation of cytotoxic CD4 T cells. These results uncover a role for Ly6Chi MOs in the modulation of CD4 T cell functions, and reveal key pathways that could be targeted to interfere with the detrimental immunopathological cascade during respiratory viral infections. Overall design: Lung MOs and CD4 T cells from C57BL/6 mice were isolated by Fluorescence-activated cell sorting (FACS) according to the presence or absence of surface markers.

γ疱疹病毒（Gammaherpesviruses, γHVs）已与其宿主共同进化数百万年，形成了极高的感染流行率，并建立了共生关系。因此，γHVs的终身持续感染似乎广泛塑造了宿主免疫状态。
本研究表明，鼠疱疹病毒4型（Murid herpesvirus 4, MuHV-4）——一种小鼠γ疱疹病毒——的肺部感染，可招募气道内的Ly6C高表达单核细胞（Ly6Chi monocytes, MOs），这类单核细胞可调控宿主免疫应答。事实上，缺失此类单核细胞会引发严重的病毒诱导性免疫病理，并伴随炎性介质的全身性释放。
机制层面，MuHV-4印记的单核细胞可招募气道内的CD4阳性T细胞（CD4 T cells），并通过PD-L1/PD-1轴（PDL1/PD-1 axis）触发免疫抑制信号通路，从而抑制细胞毒性CD4阳性T细胞（cytotoxic CD4 T cells）的有害活化。本研究揭示了Ly6C高表达单核细胞在调控CD4阳性T细胞功能中的作用，并明确了可用于干预呼吸道病毒感染过程中有害免疫病理级联反应的关键通路。
实验整体设计：通过荧光激活细胞分选术（Fluorescence-activated cell sorting, FACS），根据表面标志物的表达情况，从C57BL/6小鼠体内分离肺脏单核细胞与CD4阳性T细胞。