Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and -independent manners
Rap1 controls lymphocyte adhesion cascade and interstitial migration within lymph nodes in RAPL-dependent and -independent manners
复制标题
DOI：
10.1182/blood-2009-03-211979
复制
发表时间：
2010-01-28
期刊：
影响因子：
20.3
通讯作者：
Kinashi, Tatsuo
中科院分区：
文献类型：
--
作者：
Ebisuno, Yukihiko;Katagiri, Koko;Kinashi, Tatsuo
小分子GTP酶Rap1及其效应子RAPL调节淋巴细胞的黏附和运动。然而，它们在进入淋巴结前和间质迁移期间的粘附级联中的确切调节作用尚不清楚。在这里，我们表明，RAP1是趋化因子触发的通过LFA-1滚动淋巴细胞的初始停止步骤所必需的，而RAPL不参与快速停止。在体内，RAPL和talin在稳定淋巴细胞向血流状态下的血管内皮细胞或向外周淋巴结的高内皮微静脉阻断方面起着关键作用。此外，诱变和多肽研究表明，从LFA-1的β2细胞质区域释放反式作用抑制对于RAP1依赖的初始抑制至关重要。在体外，RAP1或RAPL缺乏严重损害淋巴细胞在淋巴结基质细胞上的运动，而RAPL缺乏则损害淋巴结内的高速定向运动。这些发现揭示了Rap1在淋巴细胞运输中的几个关键步骤，这些步骤依赖于RAPL，也不依赖于RAPL。(血。2010；115：804-814)
The small GTPase Rap1 and its effector RAPL regulate lymphocyte adhesion and motility. However, their precise regulatory roles in the adhesion cascade preceding entry into lymph nodes and during interstitial migration are unclear. Here, we show that Rap1 is indispensably required for the chemokine-triggered initial arrest step of rolling lymphocytes through LFA-1, whereas RAPL is not involved in rapid arrest. RAPL and talin play a critical role in stabilizing lymphocyte arrest to the endothelium of blood vessels under flow or to the high endothelial venules of peripheral lymph nodes in vivo. Further, mutagenesis and peptide studies suggest that release of a trans-acting restraint from the beta 2 cytoplasmic region of LFA-1 is critical for Rap1-dependent initial arrest. Rap1 or RAPL deficiency severely impaired lymphocyte motility over lymph node stromal cells in vitro, and RAPL deficiency impaired high-velocity directional movement within lymph nodes. These findings reveal the several critical steps of Rap1, which are RAPL-dependent and-independent, in lymphocyte trafficking. (Blood. 2010;115:804-814)