Institute of Molecular and Clinical Immunology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
PLoS One. 2011;6(9):e23761. doi: 10.1371/journal.pone.0023761. Epub 2011 Sep 21.
Transmembrane adaptor proteins (TRAPs) organize signaling complexes at the plasma membrane, and thus function as critical linkers and integrators of signaling cascades downstream of antigen receptors. We have previously shown that the transmembrane adaptor protein SIT regulates the threshold for thymocyte selection. Moreover, T cells from SIT-deficient mice are hyperresponsive to CD3 stimulation and undergo enhanced lymphopenia-induced homeostatic proliferation, thus indicating that SIT inhibits TCR-mediated signaling. Here, we have further addressed how SIT regulates signaling cascades in T cells. We demonstrate that the loss of SIT enhances TCR-mediated Akt activation and increased phosphorylation/inactivation of Foxo1, a transcription factor of the Forkhead family that inhibits cell cycle progression and regulates T-cell homeostasis. We have also shown that CD4(+) T cells from SIT-deficient mice display increased CD69 and CD40L expression indicating an altered activation status. Additional biochemical analyses further revealed that suppression of SIT expression by RNAi in human T cells resulted in an enhanced proximal TCR signaling. In summary, the data identify SIT as an important modulator of TCR-mediated signaling that regulates T-cell activation, homeostasis and tolerance.
跨膜衔接蛋白（TRAPs）在质膜上组织信号复合物，因此作为抗原受体下游信号级联反应的关键连接子和整合子发挥作用。我们之前已经表明，跨膜衔接蛋白 SIT 调节胸腺细胞选择的阈值。此外，SIT 缺陷小鼠的 T 细胞对 CD3 刺激反应过度，经历增强的淋巴细胞减少诱导的稳态增殖，因此表明 SIT 抑制 TCR 介导的信号转导。在这里，我们进一步研究了 SIT 如何调节 T 细胞中的信号级联反应。我们证明 SIT 的缺失增强了 TCR 介导的 Akt 激活，并增加了 Foxo1 的磷酸化/失活，Foxo1 是 Forkhead 家族的转录因子，抑制细胞周期进程并调节 T 细胞稳态。我们还表明，SIT 缺陷小鼠的 CD4(+) T 细胞显示出增加的 CD69 和 CD40L 表达，表明激活状态发生改变。进一步的生化分析还表明，在人 T 细胞中通过 RNAi 抑制 SIT 表达会导致 TCR 信号的增强。综上所述，数据表明 SIT 是调节 T 细胞激活、稳态和耐受的 TCR 介导信号转导的重要调节剂。
