IL-27 Limits Type 2 Immunopathology Following Parainfluenza Virus Infection

Respiratory paramyxoviruses are important causes of morbidity and mortality, particularly of infants and the elderly. In humans, a T helper (Th)2-biased immune response to these infections is associated with increased disease severity; however, little is known about the endogenous regulators of these responses that may be manipulated to ameliorate pathology. IL-27, a cytokine that regulates Th2 responses, is produced in the lungs during parainfluenza infection, but its role in disease pathogenesis is unknown. To determine whether IL-27 limits the development of pathogenic Th2 responses during paramyxovirus infection, IL-27-deficient or control mice were infected with the murine parainfluenza virus Sendai virus (SeV). Infected IL-27-deficient mice experienced increased weight loss, more severe lung lesions, and decreased survival compared to controls. IL-27 deficiency led to increased pulmonary eosinophils, alternatively activated macrophages (AAMs), and the emergence of Th2 responses. In control mice, IL-27 induced a population of IFN-γ+/IL-10+ CD4+ T cells that was replaced by IFN-γ+/IL-17+ and IFN-γ+/IL-13+ CD4+ T cells in IL-27-deficient mice. CD4+ T cell depletion in IL-27-deficient mice attenuated weight loss and decreased AAMs. Elimination of STAT6 signaling in IL-27-deficient mice reduced Th2 responses and decreased disease severity. These data indicate that endogenous IL-27 limits pathology during parainfluenza virus infection by regulating the quality of CD4+ T cell responses and therefore may have therapeutic potential in paramyxovirus infections.呼吸道副黏病毒是引发疾病与死亡的重要病原体，尤其对婴幼儿与老年群体危害显著。在人体中，针对这类感染的辅助性T细胞2（T helper 2, Th2）偏倚免疫应答与疾病严重程度升高相关；然而，目前对于可被用于调控以减轻病理损伤的这类应答的内源性调控因子，人们所知甚少。白细胞介素27（IL-27）是一种调控Th2应答的细胞因子，在副流感病毒感染期间可在肺部产生，但其在疾病发病机制中的作用尚不明确。为明确IL-27是否可在副黏病毒感染期间限制致病性Th2应答的产生，研究人员将IL-27基因敲除小鼠与对照小鼠分别感染鼠源副流感病毒仙台病毒（Sendai virus, SeV）。与对照组小鼠相比，感染后的IL-27基因敲除小鼠体重下降更显著，肺部病变更严重，生存率也更低。IL-27基因缺失会导致肺部嗜酸性粒细胞增多、替代性活化巨噬细胞（AAMs）水平升高，并出现Th2应答。在对照组小鼠中，IL-27可诱导产生干扰素γ（IFN-γ）+/白细胞介素10（IL-10）+ CD4+ T细胞群；而在IL-27基因敲除小鼠体内，该细胞群被干扰素γ（IFN-γ）+/白细胞介素17（IL-17）+与干扰素γ（IFN-γ）+/白细胞介素13（IL-13）+ CD4+ T细胞所取代。对IL-27基因敲除小鼠进行CD4+ T细胞清除后，其体重下降情况得到缓解，替代性活化巨噬细胞水平也有所降低。在IL-27基因敲除小鼠中阻断信号转导与转录激活因子6（STAT6）信号通路，可减弱Th2应答并减轻疾病严重程度。上述实验数据表明，内源性IL-27可通过调控CD4+ T细胞应答的质量，在副流感病毒感染期间限制病理损伤的发生，因此其在副黏病毒感染中具有潜在治疗价值。