Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States.
Division of Immunobiology, Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO, United States.
Front Immunol. 2022 Jun 29;13:916137. doi: 10.3389/fimmu.2022.916137. eCollection 2022.
Rapid re-organization of the actin cytoskeleton supports T-cell trafficking towards immune sites and interaction with antigen presenting cells (APCs). F-actin rearrangement enables T-cell trafficking by stabilizing adhesion to vascular endothelial cells and promoting transendothelial migration. T-cell/APC immune synapse (IS) maturation also relies upon f-actin-anchored LFA-1:ICAM-1 ligation. Therefore, efficient T-cell responses require tight regulation of f-actin dynamics. In this review, we summarize how the actin-bundling protein L-plastin (LPL) regulates T-cell activation and migration. LPL enhances f-actin polymerization and also directly binds to the β2 chain of the integrin LFA-1 to support intercellular adhesion and IS formation in human and murine T cells. LPL- deficient T cells migrate slowly in response to chemo-attractants such as CXCL12, CCL19, and poorly polarize towards ICAM-1. Loss of LPL impairs thymic egress and intranodal motility. LPL is also required for T-cell IS maturation with APCs, and therefore for efficient cytokine production and proliferation. LPL mice are less susceptible to T-cell mediated pathologies, such as allograft rejection and experimental autoimmune encephalomyelitis (EAE). LPL activity is regulated by its N-terminal "headpiece", which contains serine and threonine phosphorylation and calcium- and calmodulin-binding sites. LPL phosphorylation is required for lamellipodia formation during adhesion and migration, and also for LFA-1 clustering during IS formation. However, the precise molecular interactions by which LPL supports T-cell functional responses remain unclear. Future studies elucidating LPL-mediated regulation of T-cell migration and/or activation may illuminate pathways for therapeutic targeting in T-cell-mediated diseases.
肌动蛋白细胞骨架的快速重组支持 T 细胞向免疫部位的迁移和与抗原呈递细胞（APCs）的相互作用。F-肌动蛋白重排通过稳定与血管内皮细胞的粘附并促进跨内皮迁移来促进 T 细胞迁移。T 细胞/APC 免疫突触（IS）成熟也依赖于 f-肌动蛋白锚定的 LFA-1:ICAM-1 连接。因此，有效的 T 细胞反应需要严格调节 f-肌动蛋白动力学。在这篇综述中，我们总结了肌动蛋白结合蛋白 L- plastin（LPL）如何调节 T 细胞的激活和迁移。LPL 增强 f-肌动蛋白聚合，并且还直接结合整合素 LFA-1 的β2 链，以支持人和鼠 T 细胞中的细胞间粘附和 IS 形成。LPL 缺陷的 T 细胞对趋化因子（如 CXCL12、CCL19）的反应较慢，并且对 ICAM-1 的极化较差。LPL 的缺失会损害胸腺输出和淋巴结内运动。LPL 还需要与 APC 形成 T 细胞 IS 成熟，从而有效地产生细胞因子和增殖。LPL 小鼠对 T 细胞介导的病理情况（如同种异体移植物排斥和实验性自身免疫性脑脊髓炎（EAE））的敏感性较低。LPL 活性受其 N 端“头件”调节，其中包含丝氨酸和苏氨酸磷酸化以及钙和钙调蛋白结合位点。LPL 磷酸化对于粘附和迁移过程中的片状伪足形成以及 IS 形成过程中的 LFA-1 聚类是必需的。然而，LPL 支持 T 细胞功能反应的确切分子相互作用仍不清楚。阐明 LPL 介导的 T 细胞迁移和/或激活调节的未来研究可能阐明 T 细胞介导的疾病的治疗靶向途径。
