Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII
Efficient recruitment of lymphocytes in inflamed brain venules requires expression of cutaneous lymphocyte antigen and fucosyltransferase-VII
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DOI：
10.4049/jimmunol.174.9.5805
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发表时间：
2005-05-01
影响因子：
4.4
通讯作者：
Constantin, G
中科院分区：
文献类型：
--
作者：
Piccio, L;Rossi, B;Constantin, G
淋巴细胞向脑内迁移是多发性硬化及其动物模型实验性自身免疫性脑脊髓炎（EAE）发病机制中的一个关键事件。然而，控制淋巴细胞通过发炎的脑小静脉募集到CNS的机制知之甚少，因此抑制该过程的治疗方法很少。在这项研究中，我们首次证明，人类和小鼠的Th 1淋巴细胞优先粘附在小鼠发炎的脑小静脉的实验模型，模仿早期炎症在EAE。用阻断性抗P-选择素糖蛋白配体1 Ab和抗E-和P-选择素Ab观察到炎症脑小静脉中Th 1细胞的滚动和停滞的几乎完全抑制。从岩藻糖基转移酶（FucT）-IV-/-小鼠产生的Th 1淋巴细胞有效地束缚和滚动，而相比之下，从FucT-VII-/-或Fuc-VII（-/-）FucT-IV-/-小鼠获得的Th 1淋巴细胞的初级粘附急剧减少，表明FucT-VII对于炎症脑微循环中Th 1细胞的募集至关重要。重要的是，我们表明，针对皮肤淋巴细胞Ag（CLA），一个FucT-VII依赖的糖修饰的P-选择素糖蛋白配体1，阻止滚动的Th 1细胞的抗体。通过利用允许我们获得具有皮肤归巢与肠道归巢（CLA（+）与整合素β（+）（7））表型的Th 1和Th 2细胞的系统，我们观察到Th细胞上CLA的诱导表达决定了发炎脑微静脉中滚动效率的显著增加。这些观察结果使我们能够得出结论，在模拟EAE的情况下，激活的淋巴细胞向大脑的有效募集受FucT-VII及其同源细胞表面Ag CLA控制。
Lymphocyte migration into the brain represents a critical event in the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). However, the mechanisms controlling the recruitment of lymphocytes to the CNS via inflamed brain venules are poorly understood, and therapeutic approaches to inhibit this process are consequently few. In this study, we demonstrate for the first time that human and murine Th1 lymphocytes preferentially adhere to murine inflamed brain venules in an experimental model that mimics early inflammation during EAE. A virtually complete inhibition of rolling and arrest of Th1 cells in inflamed brain venules was observed with a blocking anti-P-selectin glycoprotein ligand 1 Ab and anti-E- and P-selectin Abs. Th1 lymphocytes produced from fucosyltransferase (FucT)-IV-/- mice efficiently tethered and rolled, whereas in contrast, primary adhesion of Th1 lymphocytes obtained from FucT-VII-/- or Fuc-VII(-/-)FucT-IV-/- mice was drastically reduced, indicating that FucT-VII is critical for the recruitment of Th1 cells in inflamed brain microcirculation. Importantly, we show that Abs directed against cutaneous lymphocyte Ag (CLA), a FucT-VII-dependent carbohydrate modification of P-selectin glycoprotein ligand 1, blocked rolling of Th1 cells. By exploiting a system that allowed us to obtain Th1 and Th2 cells with skin- vs gut-homing (CLA(+) vs integrin beta(+)(7)) phenotypes, we observed that induced expression of CLA on Th cells determined a striking increase of rolling efficiency in inflamed brain venules. These observations allow us to conclude that efficient recruitment of activated lymphocytes to the brain in the contexts mimicking EAE is controlled by FucT-VII and its cognate cell surface Ag CLA.