Oliphant Samantha, Lines J Louise, Hollifield Melissa L, Garvy Beth A
1 Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky , Lexington, Kentucky.
2 VA Medical Center , Lexington, Kentucky.
Viral Immunol. 2015 Dec;28(10):580-9. doi: 10.1089/vim.2015.0039. Epub 2015 Oct 26.
We previously reported that neonatal mice infected with influenza A virus (IAV) develop interstitial pneumonia characterized by reduced lung cytokine and chemokine responses. The failure of T cells to infiltrate the airways of neonates correlated with delayed clearance of sublethal IAV infections compared to adults. We hypothesized that negative regulators in the neonatal lungs such as cytokines or T regulatory (Treg) cells are responsible for these differences. Neonates either deficient in interleukin-10 (IL-10) or with T cells unresponsive to transforming growth factor-β signaling due to absence of SMAD family member 4 (Smad4) had similar IAV clearance kinetics to wild-type pups and no difference in T-cell responses. In contrast, functional depletion of Treg cells with anti-CD25 monoclonal antibody resulted in increased proportions of activated CD4(+) T cells in the lungs, but failure to clear IAV. Similarly, scurfy pups (mutation in forkhead box P3 [Foxp3] rendering them deficient in Treg cells) had increased proportions of activated T cells in the lungs compared to littermate controls. Scurfy pups also had increased proportions of IL-13-producing CD4(+) T cells. Interestingly, like anti-CD25-treated pups, scurfy pups had significantly elevated viral loads compared to controls. Based on these data, we conclude that Tregs are critical for clearance of IAV in neonatal mice.
我们之前报道过，感染甲型流感病毒（IAV）的新生小鼠会发展为间质性肺炎，其特征为肺部细胞因子和趋化因子反应减弱。与成年小鼠相比，新生小鼠T细胞无法浸润气道，这与亚致死性IAV感染的清除延迟相关。我们推测，新生小鼠肺部的负调节因子，如细胞因子或调节性T（Treg）细胞，是造成这些差异的原因。因缺乏白细胞介素-10（IL-10）或因缺少SMAD家族成员4（Smad4）而导致T细胞对转化生长因子-β信号无反应的新生小鼠，其IAV清除动力学与野生型幼崽相似，T细胞反应也无差异。相比之下，用抗CD25单克隆抗体功能性耗尽Treg细胞，会导致肺部活化CD4(+) T细胞比例增加，但无法清除IAV。同样，与同窝对照相比，毛发蓬松小鼠（叉头框P3 [Foxp3]发生突变，导致其缺乏Treg细胞）肺部活化T细胞比例增加。毛发蓬松小鼠产生IL-13的CD4(+) T细胞比例也增加。有趣的是，与抗CD25处理的幼崽一样，与对照相比，毛发蓬松小鼠的病毒载量显著升高。基于这些数据，我们得出结论，Treg细胞对新生小鼠清除IAV至关重要。
