Choi Heonsik, Cho Sung-Yup, Schwartz Ronald H, Choi Kyungho
Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 2006 May 15;176(10):6034-45. doi: 10.4049/jimmunol.176.10.6034.
Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/MAPK pathway. Several groups, however, have reported a positive role for Spry involving sequestration of the inhibitory protein c-Cbl. Thus, Spry may have various functions in the regulation of receptor-mediated signaling depending on the context. In the immune system, the function of Spry is unknown. In this study, we investigated the role of Spry1 in T cell activation. Spry1, among the four mammalian homologs, was specifically induced by TCR signaling of CD4(+) murine T cells. In fully differentiated Th1 clones, overexpressed Spry1 inhibited TCR signaling and decreased IL-2 production while reducing expression with specific siRNA transfection had the opposite effect, increasing IL-2 production. In contrast, in naive T cells, Spry1 overexpression enhanced TCR signaling, and increased proliferation and IL-2 production, while siRNA transfection again had the opposite effect, reducing IL-2 production following activation. The enhancing effect in naive cells was abrogated by preactivation of the T cells with Ag and APC, indicating that the history of exposure to Ag is correlated with a hierarchy of T cell responsiveness to Spry1. Furthermore, both the NF-AT and MAPK pathways were influenced by Spry1, implying a different molecular mechanism from that for growth factor receptor signaling. Thus, Spry1 uses a novel mechanism to bring about differential effects on TCR signaling through the same receptor, depending on the differentiation state of the T cell.
已知Sprouty（Spry）是一种通过抑制Ras/MAPK途径来负反馈抑制生长因子受体信号传导的蛋白。然而，有几个研究小组报道了Spry具有正性作用，涉及隔离抑制性蛋白c-Cbl。因此，根据具体情况，Spry在受体介导的信号调节中可能具有多种功能。在免疫系统中，Spry的功能尚不清楚。在本研究中，我们调查了Spry1在T细胞活化中的作用。在四个哺乳动物同源物中，Spry1由CD4(+)小鼠T细胞的TCR信号特异性诱导。在完全分化的Th1克隆中，过表达的Spry1抑制TCR信号传导并减少IL-2的产生，而用特异性siRNA转染降低其表达则产生相反的效果，增加IL-2的产生。相反，在未活化的T细胞中，Spry1过表达增强TCR信号传导，并增加增殖和IL-2的产生，而siRNA转染再次产生相反的效果，减少活化后IL-2的产生。T细胞用抗原和抗原呈递细胞预激活可消除未活化细胞中的增强作用，这表明接触抗原的经历与T细胞对Spry1反应性的层次相关。此外，NF-AT和MAPK途径均受Spry1影响，这意味着其分子机制与生长因子受体信号传导不同。因此，Spry1利用一种新机制，根据T细胞的分化状态，通过同一受体对TCR信号传导产生不同的影响。
