Marinari Barbara, Simeoni Luca, Schraven Burkhart, Piccolella Enza, Tuosto Loretta
Department of Cellular and Developmental Biology, La Sapienza University, I-00185 Rome, Italy.
Eur J Immunol. 2003 Sep;33(9):2609-18. doi: 10.1002/eji.200324064.
CD4-Lck recruitment to TCR/CD3, as well as Lck activation is essential for T cell activation. Indeed, the blockage of CD4-Lck recruitment to TCR during antigen recognition exerts a drastic inhibitory effect on T cell activation by interfering with both early and late phases of T cell signaling. In the present work, we report a novel inhibitory mechanism by which CD4 can shut down proximal T cell-activating signals. Indeed, we show that upon ligation of CD4 by antibodies the inhibitory kinase, p50(csk), is strongly induced and prolonged during the time. In contrast, p50(csk) was not activated when TCR and CD4 were properly engaged by their ligands. We also demonstrate that anti-CD4 treatment stimulated Csk kinase associated to the membrane adapter, PAG/Cbp, without affecting the total amount of Csk bound to PAG/Cbp. As a consequence, early tyrosine phosphorylation events as well as downstream signaling pathways leading to IL-2 gene expression induced by TCR were inhibited in anti-CD4 pretreated cells. We suggest a new model to explain the activation of negative signals by CD4 molecule.
CD4-Lck募集至TCR/CD3以及Lck激活对于T细胞激活至关重要。实际上，在抗原识别过程中，CD4-Lck募集至TCR受阻会通过干扰T细胞信号传导的早期和晚期阶段，对T细胞激活产生显著的抑制作用。在本研究中，我们报道了一种新的抑制机制，通过该机制CD4可关闭近端T细胞激活信号。事实上，我们发现用抗体连接CD4后，抑制性激酶p50(csk)会被强烈诱导并在一段时间内持续存在。相反，当TCR和CD4被其配体正确结合时，p50(csk)不会被激活。我们还证明，抗CD4处理刺激了与膜适配器PAG/Cbp相关的Csk激酶，而不影响与PAG/Cbp结合的Csk总量。因此，在抗CD4预处理的细胞中，早期酪氨酸磷酸化事件以及由TCR诱导的导致IL-2基因表达的下游信号通路均受到抑制。我们提出了一个新模型来解释CD4分子激活负信号的机制。
