Cross Talk between CD3 and CD28 Is Spatially Modulated by Protein Lateral Mobility
Cross Talk between CD3 and CD28 Is Spatially Modulated by Protein Lateral Mobility
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DOI：
10.1128/mcb.00842-13
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发表时间：
2014-03-01
影响因子：
5.3
通讯作者：
Kam, Lance C.
中科院分区：
文献类型：
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作者：
Bashour, Keenan T.;Tsai, Jones;Kam, Lance C.
CD 28共刺激和TCR信号传导的功能会聚对于T细胞活化和适应性免疫至关重要。这些受体在免疫突触内形成复杂的微观模式，尽管这种空间组织对细胞信号传导的影响仍不清楚。我们调查这种串扰使用微图案化的表面，目前这些膜蛋白的配体，以控制组织内的细胞基质界面的信号分子。虽然原代人CD 4（+）T细胞被含有CD 3和CD 28配体的特征激活，但在这两个系统的接合被微米级距离分开的表面上，这种功能收敛被削弱。此外，磷酸化的Lck被集中到CD 3接合的区域，并表现出低扩散速率，这表明共刺激是由活性Lck向CD 28的转运及其失活之间的平衡控制的。在这个模型的支持下，破坏肌动蛋白细胞骨架增加Lck的流动性，并允许功能性T细胞的空间分离的CD 3和CD 28的共刺激。在原代小鼠CD 4（+）T细胞中，一种互补系统，降低膜迁移率增加了对CD 3-CD 28分离的敏感性。这些结果表明，亚细胞反应扩散系统，使细胞能够感觉到细胞外环境的微观组织。
Functional convergence of CD28 costimulation and TCR signaling is critical to T-cell activation and adaptive immunity. These receptors form complex microscale patterns within the immune synapse, although the impact of this spatial organization on cell signaling remains unclear. We investigate this cross talk using micropatterned surfaces that present ligands to these membrane proteins in order to control the organization of signaling molecules within the cell-substrate interface. While primary human CD4(+) T cells were activated by features containing ligands to both CD3 and CD28, this functional convergence was curtailed on surfaces in which engagement of these two systems was separated by micrometer-scale distances. Moreover, phosphorylated Lck was concentrated to regions of CD3 engagement and exhibited a low diffusion rate, suggesting that costimulation is controlled by a balance between the transport of active Lck to CD28 and its deactivation. In support of this model, disruption of the actin cytoskeleton increased Lck mobility and allowed functional T-cell costimulation by spatially separated CD3 and CD28. In primary mouse CD4(+) T cells, a complementary system, reducing the membrane mobility increased the sensitivity to CD3-CD28 separation. These results demonstrate a subcellular reaction-diffusion system that allows cells to sense the microscale organization of the extracellular environment.