Table_1_LFA-1 Controls Th1 and Th17 Motility Behavior in the Inflamed Central Nervous System.pdf

Leukocyte trafficking is a key event during autoimmune and inflammatory responses. The subarachnoid space (SAS) and cerebrospinal fluid are major routes for the migration of encephalitogenic T cells into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, and are sites of T cell activation before the invasion of CNS parenchyma. In particular, autoreactive Th1 and Th17 cell trafficking and reactivation in the CNS are required for the pathogenesis of EAE. However, the molecular mechanisms controlling T cell dynamics during EAE are unclear. We used two-photon laser microscopy to show that autoreactive Th1 and Th17 cells display distinct motility behavior within the SAS in the spinal cords of mice immunized with the myelin oligodendrocyte glycoprotein peptide MOG35−55. Th1 cells showed a strong directional bias at the disease peak, moving in a straight line and covering long distances, whereas Th17 cells exhibited more constrained motility. The dynamics of both Th1 and Th17 cells were strongly affected by blocking the integrin LFA-1, which interfered with the deformability and biomechanics of Th1 but not Th17 cells. The intrathecal injection of a blocking anti-LFA-1 antibody at the onset of disease significantly inhibited EAE progression and also strongly reduced neuro-inflammation in the immunized mice. Our results show that LFA-1 plays a pivotal role in T cell motility during EAE and suggest that interfering with the molecular mechanisms controlling T cell motility can help to reduce the pathogenic potential of autoreactive lymphocytes.

白细胞迁移是自身免疫与炎症应答过程中的关键事件。蛛网膜下腔（subarachnoid space, SAS）与脑脊液是实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis, EAE，多发性硬化的动物模型）中致脑炎T细胞向中枢神经系统（central nervous system, CNS）迁移的主要通路，同时也是中枢神经系统实质侵袭前T细胞活化的场所。尤为关键的是，自身反应性Th1与Th17细胞在中枢神经系统内的迁移与再活化，是EAE发病机制的必要条件。然而，EAE进程中调控T细胞动态行为的分子机制仍不明晰。本研究借助双光子激光显微镜术发现，在经髓鞘少突胶质细胞糖蛋白肽段MOG35−55免疫的小鼠脊髓蛛网膜下腔内，自身反应性Th1与Th17细胞展现出截然不同的运动行为：在疾病高峰期，Th1细胞呈现显著的定向偏向性，以直线运动方式长距离迁移；而Th17细胞则表现出更为受限的运动模式。阻断整合素LFA-1可显著影响两类细胞的动态行为，该干预会干扰Th1细胞的变形能力与生物力学特性，但对Th17细胞并无此类作用。在疾病发作期鞘内注射抗LFA-1阻断抗体，可显著抑制EAE的病情进展，并大幅减轻免疫小鼠的神经炎症反应。本研究结果表明，整合素LFA-1在EAE进程中的T细胞运动中发挥关键作用，同时提示，靶向调控T细胞运动的分子机制，有望降低自身反应性淋巴细胞的致病潜能。