Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Proc Natl Acad Sci U S A. 2021 May 4;118(18). doi: 10.1073/pnas.2023230118.
The a disintegrin and metalloproteinase (ADAM) family of proteinases alter the extracellular environment and are involved in the development of T cells and autoimmunity. The role of ADAM family members in Th17 cell differentiation is unknown. We identified ADAM9 to be specifically expressed and to promote Th17 differentiation. Mechanistically, we found that ADAM9 cleaved the latency-associated peptide to produce bioactive transforming growth factor β1, which promoted SMAD2/3 phosphorylation and activation. A transcription factor inducible cAMP early repressor was found to bind directly to the promoter and to promote its transcription. -deficient mice displayed mitigated experimental autoimmune encephalomyelitis, and transfer of -deficient myelin oligodendrocyte globulin-specific T cells into mice failed to induce disease. At the translational level, an increased abundance of ADAM9 levels was observed in CD4 T cells from patients with systemic lupus erythematosus, and ADAM9 gene deletion in lupus primary CD4 T cells clearly attenuated their ability to differentiate into Th17 cells. These findings revealed that ADAM9 as a proteinase provides Th17 cells with an ability to activate transforming growth factor β1 and accelerates its differentiation, resulting in aberrant autoimmunity.
去整合素金属蛋白酶（ADAM）家族的蛋白酶改变细胞外环境，并参与 T 细胞的发育和自身免疫。ADAM 家族成员在 Th17 细胞分化中的作用尚不清楚。我们发现 ADAM9 特异性表达并促进 Th17 分化。从机制上讲，我们发现 ADAM9 切割潜伏相关肽以产生生物活性转化生长因子β1，促进 SMAD2/3 磷酸化和激活。发现诱导型 cAMP 早期阻遏转录因子直接结合启动子并促进其转录。-缺陷小鼠表现出实验性自身免疫性脑脊髓炎的缓解，并且将 -缺陷的髓鞘少突胶质细胞糖蛋白特异性 T 细胞转移到 缺陷小鼠中未能诱导疾病。在翻译水平上，系统性红斑狼疮患者的 CD4 T 细胞中观察到 ADAM9 水平的增加，狼疮原代 CD4 T 细胞中的 ADAM9 基因缺失明显减弱了它们分化为 Th17 细胞的能力。这些发现表明 ADAM9 作为一种蛋白酶为 Th17 细胞提供了激活转化生长因子β1 的能力，并加速了其分化，导致异常的自身免疫。
