Morrison Vicky Louise, Uotila Liisa M, Llort Asens Marc, Savinko Terhi, Fagerholm Susanna Carola
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;
Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland; Medical Research Institute, University of Dundee, Dundee DD1 9SY, United Kingdom; and Faculty of Biological and Environmental Sciences, University of Helsinki, 00014 Helsinki, Finland
J Immunol. 2015 Jul 1;195(1):105-15. doi: 10.4049/jimmunol.1402741. Epub 2015 May 18.
Kindlin-3 is an important integrin regulator that is mutated in the rare genetic disorder, leukocyte adhesion deficiency type III, a disorder characterized by defective neutrophil trafficking and platelet function, leading to recurrent bacterial infections and bleeding. Kindlin-3 is also known to regulate T cell adhesion in vitro and trafficking in vivo, but whether the integrin/kindlin interaction regulates T or B cell activation in vivo is unclear. In this study, we used TTT/AAA β2-integrin knock-in (KI) mice and TCR-transgenic (OT-II) KI mice, in which the integrin/kindlin connection is disrupted, to investigate the role of the integrin/kindlin interaction in T cell activation. We show that basal T cell activation status in these animals in vivo is normal, but they display reduced T cell activation by wild-type Ag-loaded dendritic cells in vitro. In addition, T cell activation in vivo is reduced. We also show that basal Ab levels are normal in TTT/AAA β2-integrin KI mice, but B cell numbers in lymph nodes and IgG and IgM production after immunization are reduced. In conclusion, we show that the integrin/kindlin interaction is required for trafficking of immune cells, as well as for T cell activation and B cell Ab responses in vivo. These results imply that the immunodeficiency found in leukocyte adhesion deficiency type III patients, in addition to being caused by defects in neutrophil function, may be due, in part, to defects in lymphocyte trafficking and activation.
Kindlin-3是一种重要的整合素调节因子，在罕见的遗传性疾病III型白细胞黏附缺陷中发生突变，该疾病的特征是中性粒细胞运输和血小板功能缺陷，导致反复细菌感染和出血。已知Kindlin-3在体外调节T细胞黏附，在体内调节T细胞运输，但整合素/Kindlin相互作用是否在体内调节T细胞或B细胞活化尚不清楚。在本研究中，我们使用了TTT/AAA β2整合素敲入（KI）小鼠和TCR转基因（OT-II）KI小鼠，其中整合素/Kindlin连接被破坏，以研究整合素/Kindlin相互作用在T细胞活化中的作用。我们发现，这些动物体内的基础T细胞活化状态正常，但在体外它们对负载野生型抗原的树突状细胞的T细胞活化反应降低。此外，体内T细胞活化也减少。我们还发现，TTT/AAA β2整合素KI小鼠的基础抗体水平正常，但免疫后淋巴结中的B细胞数量以及IgG和IgM的产生减少。总之，我们表明整合素/Kindlin相互作用是免疫细胞运输以及体内T细胞活化和B细胞抗体反应所必需的。这些结果表明，III型白细胞黏附缺陷患者中发现的免疫缺陷，除了由中性粒细胞功能缺陷引起外，可能部分归因于淋巴细胞运输和活化缺陷。
