Institute of Molecular and Clinical Immunology, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-von-Guericke-University, Magdeburg, Germany.
Institute of Biology, Department of Genetics and Molecular Neurobiology, Otto-von-Guericke University, Magdeburg, Germany.
Front Immunol. 2018 Dec 4;9:2852. doi: 10.3389/fimmu.2018.02852. eCollection 2018.
The integrin LFA-1 (CD11a/CD18) plays a critical role in the interaction of T cells with antigen presenting cells (APCs) to promote lymphocyte differentiation and proliferation. This integrin can be present either in a closed or in an open active conformation and its activation upon T-cell receptor (TCR) stimulation is a critical step to allow interaction with APCs. In this study we demonstrate that the serine/threonine kinase Ndr2 is critically involved in the initiation of TCR-mediated LFA-1 activation (open conformation) in T cells. Ndr2 itself becomes activated upon TCR stimulation and phosphorylates the intracellular integrin binding partner Filamin A (FLNa) at serine 2152. This phosphorylation promotes the dissociation of FLNa from LFA-1, allowing for a subsequent association of Talin and Kindlin-3 which both stabilize the open conformation of LFA-1. Our data suggest that Ndr2 activation is a crucial step to initiate TCR-mediated LFA-1 activation in T cells.
整合素 LFA-1（CD11a/CD18）在 T 细胞与抗原呈递细胞（APCs）相互作用中发挥关键作用，促进淋巴细胞分化和增殖。这种整合素可以处于关闭或开放的活性构象，其在 T 细胞受体（TCR）刺激下的激活是允许与 APCs 相互作用的关键步骤。在这项研究中，我们证明丝氨酸/苏氨酸激酶 Ndr2 是 TCR 介导的 LFA-1 激活（开放构象）在 T 细胞中起始的关键因素。Ndr2 自身在 TCR 刺激下被激活，并在丝氨酸 2152 处磷酸化细胞内整合素结合伴侣细丝蛋白 A（FLNa）。这种磷酸化促进了 FLNa 与 LFA-1 的解离，随后允许 TALIN 和 KINDLIN-3 的结合，它们都稳定 LFA-1 的开放构象。我们的数据表明，Ndr2 的激活是启动 T 细胞 TCR 介导的 LFA-1 激活的关键步骤。
