Division of Rheumatology, Department of Medicine, Beth Israel Deaconess MedicalCenter, Harvard Medical School, Boston, Massachusetts 02215, USA.
J Biol Chem. 2012 Nov 2;287(45):38168-77. doi: 10.1074/jbc.M112.415067. Epub 2012 Sep 18.
Th17 lymphocytes play a key role during immune responses against bacteria and fungi and are involved in the pathophysiology of multiple autoimmune disorders. The co-stimulatory molecules SLAMF3 and SLAMF6 have been implicated in the formation of Th17 phenotypes and IL-17A expression. Increased surface expression of SLAMF3 and SLAMF6 has been linked with disease activity in systemic lupus erythematosus. Here we demonstrate that in human total T lymphocytes the canonical CD28 and the non-canonical SLAMF3/SLAMF6 co-stimulatory pathways cooperate in the recruitment of the transcription factor NFAT1 to the IL17A promoter. Furthermore, the dominance of the SLAMF3/SLAMF6 pathway in inducing IL-17A production can be attributed to an increased nuclear abundance and recruitment of RORγt to the IL17A promoter. Thus, we have identified an additional mechanism that may be central for the specific control of IL17A gene regulation in systemic lupus erythematosus T lymphocytes.
Th17 淋巴细胞在针对细菌和真菌的免疫反应中发挥关键作用，并且参与多种自身免疫性疾病的病理生理学。共刺激分子 SLAMF3 和 SLAMF6 被认为参与了 Th17 表型和 IL-17A 表达的形成。SLAMF3 和 SLAMF6 的表面表达增加与系统性红斑狼疮的疾病活动度相关。在这里，我们证明在人类总 T 淋巴细胞中，经典的 CD28 和非经典的 SLAMF3/SLAMF6 共刺激途径共同招募转录因子 NFAT1 到 IL17A 启动子。此外，SLAMF3/SLAMF6 途径诱导 IL-17A 产生的优势可以归因于核内 RORγt 的丰度增加和招募到 IL17A 启动子。因此，我们已经确定了另一种可能在系统性红斑狼疮 T 淋巴细胞中对 IL17A 基因调控的特异性控制起核心作用的机制。
