Hwang Il-Young, Park Chung, Harrison Kathleen, Kehrl John H
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
J Immunol. 2017 Apr 1;198(7):2721-2734. doi: 10.4049/jimmunol.1601433. Epub 2017 Feb 24.
Adaptive immunity depends on mature thymocytes leaving the thymus to enter the bloodstream and the trafficking of T cells through lymphoid organs. Both of these require heterotrimeric Gα protein signaling, whose intensity and duration are controlled by the regulator of G protein signaling (RGS) proteins. In this study, we show that RGS protein/Gα interactions are essential for normal thymocyte egress, T cell trafficking, and homeostasis. Mature thymocytes with a Gα mutation that disables RGS protein binding accumulated in the perivascular channels of thymic corticomedullary venules. Severe reductions in peripheral naive CD4 T cells and regulatory T cells occurred. The mutant CD4 T cells adhered poorly to high endothelial venules and exhibited defects in lymph node entrance and egress. The kinetics of chemokine receptor signaling were disturbed, including chemokine- induced integrin activation. Despite the thymic and lymph node egress defects, sphingosine-1-phosphate signaling was not obviously perturbed. This study reveals how RGS proteins modulate Gα signaling to facilitate thymocyte egress and T cell trafficking.
适应性免疫依赖于成熟胸腺细胞离开胸腺进入血液循环以及T细胞通过淋巴器官的迁移。这两者都需要异源三聚体Gα蛋白信号传导，其强度和持续时间由G蛋白信号调节（RGS）蛋白控制。在本研究中，我们表明RGS蛋白/Gα相互作用对于正常胸腺细胞输出、T细胞迁移和体内平衡至关重要。具有使RGS蛋白结合失能的Gα突变的成熟胸腺细胞积聚在胸腺皮质髓质小静脉的血管周围通道中。外周幼稚CD4 T细胞和调节性T细胞严重减少。突变的CD4 T细胞与高内皮小静脉的粘附性差，并在淋巴结进入和离开方面表现出缺陷。趋化因子受体信号传导的动力学受到干扰，包括趋化因子诱导的整合素激活。尽管存在胸腺和淋巴结输出缺陷，但1-磷酸鞘氨醇信号传导并未明显受到干扰。这项研究揭示了RGS蛋白如何调节Gα信号传导以促进胸腺细胞输出和T细胞迁移。
