F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse.
F-actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse.
复制标题
DOI：
10.1083/jcb.201406121
复制
发表时间：
2015-02-16
期刊：
影响因子：
--
通讯作者：
Burkhardt JK
中科院分区：
文献类型：
--
作者：
Comrie WA;Babich A;Burkhardt JK
T细胞肌动蛋白网络产生调节免疫突触处LFA-1活性的机械力。T细胞和抗原呈递细胞之间的整合素依赖性相互作用对于适当的T细胞活化、效应器功能和记忆至关重要。整联蛋白功能的调节通过构象变化发生，构象变化调节配体亲和力，受体聚集调节化合价。在这里，我们表明，白细胞功能抗原1（LFA-1）的构象中间体形成一个同心阵列的免疫突触。使用抑制剂鸡尾酒逮捕F-肌动蛋白动力学，我们表明，该阵列的组织取决于F-肌动蛋白的流动和配体的流动性。此外，F-肌动蛋白流动对于维持LFA-1的高亲和力构象、通过将LFA-1募集到免疫突触来增加效价以及最终促进细胞内细胞粘附分子1（ICAM-1）结合是至关重要的。最后，我们表明，F-肌动蛋白的力量是反对固定的ICAM-1，触发LFA-1激活通过诱导适合和张力为基础的机制相结合。我们的数据提供了直接支持的模型中，T细胞肌动蛋白网络产生的机械力，调节LFA-1的活性在免疫突触。
The T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse. Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. Regulation of integrin function occurs via conformational change, which modulates ligand affinity, and receptor clustering, which modulates valency. Here, we show that conformational intermediates of leukocyte functional antigen 1 (LFA-1) form a concentric array at the immunological synapse. Using an inhibitor cocktail to arrest F-actin dynamics, we show that organization of this array depends on F-actin flow and ligand mobility. Furthermore, F-actin flow is critical for maintaining the high affinity conformation of LFA-1, for increasing valency by recruiting LFA-1 to the immunological synapse, and ultimately for promoting intracellular cell adhesion molecule 1 (ICAM-1) binding. Finally, we show that F-actin forces are opposed by immobilized ICAM-1, which triggers LFA-1 activation through a combination of induced fit and tension-based mechanisms. Our data provide direct support for a model in which the T cell actin network generates mechanical forces that regulate LFA-1 activity at the immunological synapse.
登录
查看更多内容
DOI：
10.1083/jcb.201406120
发表时间：
2015-02-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Comrie WA;Li S;Boyle S;Burkhardt JK
通讯作者：
Burkhardt JK
DOI：
10.1083/jcb.201201018
发表时间：
2012-06-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Babich A;Li S;O'Connor RS;Milone MC;Freedman BD;Burkhardt JK
通讯作者：
Burkhardt JK
影响因子：
3.4
作者：
Judokusumo, Edward;Tabdanov, Erdem;Kam, Lance C.
通讯作者：
Kam, Lance C.
DOI：
10.3109/15419069809004481
发表时间：
1998-01-01
期刊：
CELL ADHESION AND COMMUNICATION
影响因子：
--
作者：
Dustin, ML
通讯作者：
Dustin, ML
DOI：
10.1073/pnas.0902621106
发表时间：
2009-08-04
影响因子：
11.1
作者：
Hartman, Nina C.;Nye, Jeffrey A.;Groves, Jay T.
通讯作者：
Groves, Jay T.