LFA-1-Mediated T cell costimulation through increased localization of TCR/Class II complexes to the central supramolecular activation cluster and exclusion of CD45 from the immunological synapse
LFA-1-Mediated T cell costimulation through increased localization of TCR/Class II complexes to the central supramolecular activation cluster and exclusion of CD45 from the immunological synapse
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DOI：
10.4049/jimmunol.179.3.1616
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发表时间：
2007-08-01
影响因子：
4.4
通讯作者：
Miller, Jim
中科院分区：
文献类型：
--
作者：
Graf, Beth;Bushnell, Timothy;Miller, Jim
T细胞活化与T细胞：APC缀合物中的免疫突触内的细胞表面蛋白和相关信号传导组分的显著重组相关。然而，指导这些蛋白质定位的信号和该组织的功能意义尚未确定。在这项研究中，我们使用野生型和LFA-1缺陷型，D011.10 TCR转基因T细胞来检查LFA-1在免疫突触形成中的作用。我们发现LFA-1的共同参与对于中央超分子活化簇（cSMAC）区域的形成不是必需的，但确实增加了cSMAC内TCR/II类复合物的积累。此外，LFA-1是必需的招募和本地化talin进入外周超分子活化簇区域和排斥的CD 45从突触。LFA-1能够增加突触形成过程中参与的TCR的量，并将磷酸酶CD 45从突触中分离出来，这表明LFA-1可能增强近端TCR信号传导。为了测试这一点，我们结合了流式细胞术为基础的细胞粘附和钙信号转导试验，发现LFA-1的共同参与显着增加了Ag呈递后细胞内钙反应的幅度。这些数据支持这样的观点，即除了其在调节T细胞：APC粘附上的重要作用之外，LFA-1的共同参与可以增强T细胞信号传导，并且表明这可能部分地通过免疫突触内的蛋白质组织来实现。
T cell activation is associated with a dramatic reorganization of cell surface proteins and associated signaling components into discrete subdomains within the immunological synapse in T cell:APC conjugates. However, the signals that direct the localization of these proteins and the functional significance of this organization have not been established. In this study, we have used wild-type and LFA-1-deficient, D011.10 TCR transgenic T cells to examine the role of LFA-1 in the formation of the immunological synapse. We found that coengagement of LFA-1 is not required for the formation of the central supramolecular activation cluster (cSMAC) region, but does increase the accumulation of TCR/class II complexes within the cSMAC. In addition, LFA-1 is required for the recruitment and localization of talin into the peripheral supramolecular activation cluster region and exclusion of CD45 from the synapse. The ability of LFA-1 to increase the amount of TCR engaged during synapse formation and segregate the phosphatase, CD45, from the synapse suggests that LFA-1 might enhance proximal TCR signaling. To test this, we combined flow cytometry-based cell adhesion and calcium-signaling assays and found that coengagement of LFA-1 significantly increased the magnitude of the intracellular calcium response following Ag presentation. These data support the idea that in addition to its important role on regulating T cell:APC adhesion, coengagement of LFA-1 can enhance T cell signaling, and suggest that this may be accomplished in part through the organization of proteins within the immunological synapse.