Acinetobacter lwoffii exposure promotes PD-L1+ neutrophils and dampens viral-induced type 2 immunity

Severe, recurrent viral infections in early life, such as those caused by
respiratory syncytial virus (RSV) are associated with wheezing and asthma.
Exposure to farmyard microbes protects against allergen-induced asthma,
but their role in viral-induced airways disease is less understood. Here
neonatal murine recurrent RSV infection promoted pulmonary eosinophilia,
mucus hypersecretion and IL-13+ CD4+ T cells. These pathological features
were ameliorated by concomitant inhalation of inactivated cowshed-derived
bacteria, Acinetobacter lwoffii F78. The protective effect was maximal
with continuous A.lwoffii exposure and protection correlated with
increased circulatory, airway and lung parenchymal neutrophils. However,
in contrast to pro-inflammatory neutrophils induced by RSV infection,
transcriptomic and phenotypic analysis revealed A.lwoffii induced a
distinct neutrophil population with reduced expression of CXCR4 and CD101,
but elevated PD-L1. Induction of these PD-L1+ immunoregulatory neutrophils
by inhaled A.lwoffii was linked to a concomitant reduction in Th2
immunity.

生命早期罹患的重症复发性病毒感染，例如由呼吸道合胞病毒（Respiratory Syncytial Virus, RSV）引发的感染，与喘息及哮喘存在显著关联。接触农场微生物可预防过敏原诱导的哮喘，但此类微生物在病毒诱发的气道疾病中所发挥的作用仍不甚明确。本研究中，新生小鼠反复感染呼吸道合胞病毒可诱发肺部嗜酸性粒细胞增多、黏液过度分泌以及IL-13阳性CD4阳性T细胞（IL-13+ CD4+ T cells）的增多。若在感染同时吸入灭活的牛棚来源细菌——路邓不动杆菌（Acinetobacter lwoffii）F78，则可改善上述病理特征。持续暴露于路邓不动杆菌可使该保护效应达到最强，且保护作用与循环系统、气道及肺实质内中性粒细胞的增多呈正相关。然而，与RSV感染诱导的促炎性中性粒细胞不同，转录组学与表型分析显示，路邓不动杆菌可诱导出一类独特的中性粒细胞群：其CXC趋化因子受体4（CXCR4）与分化簇101（CD101）的表达水平降低，而程序性死亡受体配体1（PD-L1）的表达水平升高。吸入路邓不动杆菌诱导产生的这类PD-L1阳性免疫调节性中性粒细胞，与辅助性T细胞2型（Th2）免疫反应的减弱密切相关。