Glanville Nicholas, Peel Tamlyn J, Schröder Armin, Aniscenko Julia, Walton Ross P, Finotto Susetta, Johnston Sebastian L
Airway Disease Infection Section, National Heart and Lung Institute, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Imperial College London, London, United Kingdom.
Laboratory of Cellular and Molecular Lung Immunology, Department of Molecular Pneumology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
PLoS Pathog. 2016 Sep 28;12(9):e1005913. doi: 10.1371/journal.ppat.1005913. eCollection 2016 Sep.
Current understanding of adaptive immune, particularly T cell, responses to human rhinoviruses (RV) is limited. Memory T cells are thought to be of a primarily T helper 1 type, but both T helper 1 and T helper 2 memory cells have been described, and heightened T helper 2/ lessened T helper 1 responses have been associated with increased RV-induced asthma exacerbation severity. We examined the contribution of T helper 1 cells to RV-induced airways inflammation using mice deficient in the transcription factor T-Box Expressed In T Cells (Tbet), a critical controller of T helper 1 cell differentiation. Using flow cytometry we showed that Tbet deficient mice lacked the T helper 1 response of wild type mice and instead developed mixed T helper 2/T helper 17 responses to RV infection, evidenced by increased numbers of GATA binding protein 3 (GATA-3) and RAR-related orphan receptor gamma t (RORγt), and interleukin-13 and interleukin-17A expressing CD4+ T cells in the lung. Forkhead box P3 (FOXP3) and interleukin-10 expressing T cell numbers were unaffected. Tbet deficient mice also displayed deficiencies in lung Natural Killer, Natural Killer T cell and γδT cell responses, and serum neutralising antibody responses. Tbet deficient mice exhibited pronounced airways eosinophilia and mucus production in response to RV infection that, by utilising a CD4+ cell depleting antibody, were found to be T helper cell dependent. RV induction of T helper 2 and T helper 17 responses may therefore have an important role in directly driving features of allergic airways disease such as eosinophilia and mucus hypersecretion during asthma exacerbations.
目前对于适应性免疫，尤其是T细胞对人鼻病毒（RV）的反应的了解有限。记忆T细胞被认为主要是辅助性T细胞1型，但辅助性T细胞1型和辅助性T细胞2型记忆细胞均有报道，并且辅助性T细胞2型反应增强/辅助性T细胞1型反应减弱与RV诱导的哮喘加重严重程度增加有关。我们使用转录因子T细胞表达的T盒（Tbet）缺陷小鼠研究了辅助性T细胞1型对RV诱导的气道炎症的作用，Tbet是辅助性T细胞1型分化的关键调控因子。通过流式细胞术我们发现，Tbet缺陷小鼠缺乏野生型小鼠的辅助性T细胞1型反应，而是对RV感染产生了混合的辅助性T细胞2型/辅助性T细胞17型反应，肺中表达GATA结合蛋白3（GATA-3）和视黄酸相关孤儿受体γt（RORγt）以及白细胞介素-13和白细胞介素-17A的CD4 + T细胞数量增加证明了这一点。表达叉头框P3（FOXP3）和白细胞介素-10的T细胞数量未受影响。Tbet缺陷小鼠在肺自然杀伤细胞、自然杀伤T细胞和γδT细胞反应以及血清中和抗体反应方面也存在缺陷。Tbet缺陷小鼠在受到RV感染后表现出明显的气道嗜酸性粒细胞增多和黏液产生，通过使用CD4 +细胞耗竭抗体发现这是辅助性T细胞依赖性的。因此，RV诱导的辅助性T细胞2型和辅助性T细胞17型反应可能在哮喘加重期间直接驱动过敏性气道疾病的特征，如嗜酸性粒细胞增多和黏液分泌过多方面发挥重要作用。
