David H Smith Center for Vaccine Biology and Immunology, Aab Institute of Biomedical Sciences, University of Rochester Medical Center, Rochester, NY 14642, USA.
J Immunol. 2011 Dec 1;187(11):5515-9. doi: 10.4049/jimmunol.1102497. Epub 2011 Nov 7.
Efficient T cell activation depends on the engagement of both TCR and CD28, although the molecular mechanisms that control this signal integration are not fully understood. Using fluorescence resonance energy transfer, we show that T cell activation can drive a reorientation of the cytosolic tails of the CD28 dimer. However, this is not mediated through CD28 ligand binding. Rather, TCR signaling itself mediates this conformation change in CD28. We also show that TCR signaling can induce CD28-ligand interactions. Although the CD28 dimer appears to bind ligand monovalently in solution, we show that both ligand binding sites are required to efficiently recruit CD28 to the immunological synapse. These results suggest, that analogous to the cross-talk from TCR that regulates integrin activation, TCR-initiated inside-out signaling may induce a conformational change to the extracellular domains of CD28, enabling ligand binding and initiating CD28 signaling.
有效的 T 细胞激活依赖于 TCR 和 CD28 的共同参与，尽管控制这种信号整合的分子机制尚未完全阐明。我们利用荧光共振能量转移技术显示，T 细胞激活可以驱动 CD28 二聚体胞质尾部的重定向。然而，这不是通过 CD28 配体结合介导的。相反，TCR 信号本身介导了 CD28 的这种构象变化。我们还表明，TCR 信号可以诱导 CD28-配体相互作用。尽管 CD28 二聚体在溶液中似乎以单价结合配体，但我们表明，配体结合位点都需要有效地将 CD28 募集到免疫突触。这些结果表明，类似于调节整合素激活的 TCR 串扰，TCR 起始的内向外信号转导可能诱导 CD28 胞外结构域的构象变化，从而允许配体结合并启动 CD28 信号转导。
