Attenuation of Immune-Mediated Influenza Pneumonia by Targeting the Inducible Co-Stimulator (ICOS) Molecule on T Cells

Inducible Co-stimulator (ICOS) plays a critical role in mediating T cell differentiation and function and is considered a key player in balancing T effector and T regulatory (Treg) cell responses. Here we show that activation of the ICOS signalling pathway during acute influenza A virus (IAV) infection by application of an agonistic ICOS antibody reduced the frequency of CD8+ T cells in the respiratory tract of IAV infected animals and delayed pathogen elimination. In line with this, immune-mediated influenza pneumonia was significantly ameliorated in mice that received ICOS agonist as indicated by significantly reduced alveolar infiltrations and bronchointerstitial pneumonia, while at the same time virus-related pathology remained unaffected. Importantly, ICOS agonist treatment resulted in expansion of CD4+Foxp3+ Tregs in IAV infected mice, which was associated with elevated levels of the immunosuppressive cytokine IL-10 in the alveolar space. Together, our findings suggest a prominent role of ICOS signaling during acute IAV infection by increasing the Treg/CD8+ T cell ratio with beneficial outcome on immune-mediated pneumonia and underline the suitability of ICOS as potential therapeutic target for immune intervention in those infectious conditions characterized by strong immunopathology rather than virus-mediated cytopathic effects.

诱导性共刺激分子（Inducible Co-stimulator, ICOS）在介导T细胞分化与功能中发挥关键作用，被认为是维持效应T细胞与调节性T细胞（Treg）应答平衡的核心参与者。本研究显示，在甲型流感病毒（influenza A virus, IAV）急性感染期间，通过给予ICOS激动性抗体激活ICOS信号通路，会降低IAV感染动物呼吸道内CD8+T细胞的比例，并延缓病原体清除。与此一致的是，接受ICOS激动剂处理的小鼠，其免疫介导性流感肺炎得到显著改善，表现为肺泡浸润与支气管间质性肺炎明显减轻，而病毒相关病理损伤则未受影响。值得注意的是，ICOS激动剂处理可使IAV感染小鼠体内的CD4+Foxp3+调节性T细胞发生扩增，这与肺泡腔内免疫抑制性细胞因子IL-10水平升高相关。综上，本研究结果表明，急性IAV感染期间，ICOS信号通路可通过提高Treg与CD8+T细胞的比值，对免疫介导性肺炎产生有益影响，同时凸显了ICOS作为潜在治疗靶点的适用性，可用于干预那些以强烈免疫病理而非病毒介导细胞病变效应为特征的感染性疾病。