Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
Immunity. 2010 Sep 24;33(3):326-39. doi: 10.1016/j.immuni.2010.09.006.
T cell activation is positively and negatively regulated by a pair of costimulatory receptors, CD28 and CTLA-4, respectively. Because these receptors share common ligands, CD80 and CD86, the expression and behavior of CTLA-4 is critical for T cell costimulation regulation. However, in vivo blocking of CD28-mediated costimulation by CTLA-4 and its mechanisms still remain elusive. Here, we demonstrate the dynamic behavior of CTLA-4 in its real-time competition with CD28 at the central-supramolecular activation cluster (cSMAC), resulting in the dislocalization of protein kinase C-θ and CARMA1 scaffolding protein. CTLA-4 translocation to the T cell receptor microclusters and the cSMAC is tightly regulated by its ectodomain size, and its accumulation at the cSMAC is required for its inhibitory function. The CTLA-4-mediated suppression was demonstrated by the in vitro anergy induction in regulatory T cells constitutively expressing CTLA-4. These results show the dynamic mechanism of CTLA-4-mediated T cell suppression at the cSMAC.
T 细胞的激活受一对共刺激受体 CD28 和 CTLA-4 的正调控和负调控。由于这些受体共享共同的配体 CD80 和 CD86，因此 CTLA-4 的表达和行为对于 T 细胞共刺激调节至关重要。然而，体内 CTLA-4 阻断 CD28 介导的共刺激及其机制仍然难以捉摸。在这里，我们证明了 CTLA-4 在中央超分子激活簇（cSMAC）中与 CD28 的实时竞争中的动态行为，导致蛋白激酶 C-θ和 CARMA1 支架蛋白的去本地化。CTLA-4 易位到 TCR 微簇和 cSMAC 受到其胞外结构域大小的严格调节，其在 cSMAC 中的积累对于其抑制功能是必需的。通过在持续表达 CTLA-4 的调节性 T 细胞中体外诱导无能来证明 CTLA-4 介导的抑制作用。这些结果显示了 CTLA-4 在 cSMAC 介导的 T 细胞抑制的动态机制。
