The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.
The TGF-β superfamily cytokine Activin-A is induced during autoimmune neuroinflammation and drives pathogenic Th17 cell differentiation.
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DOI：
10.1016/j.immuni.2020.12.010
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发表时间：
2021-02-09
期刊：
影响因子：
32.4
通讯作者：
Wan YY
中科院分区：
文献类型：
--
作者：
Wu B;Zhang S;Guo Z;Bi Y;Zhou M;Li P;Seyedsadr M;Xu X;Li JL;Markovic-Plese S;Wan YY
已知Th 17细胞发挥致病性和非致病性功能。虽然细胞因子TGF-β1有助于Th 17细胞分化，但它对于致病性Th 17细胞的产生是不可缺少的。在此，我们研究了活化素A（一种与TGF-β1密切相关的TGF-β超家族成员）在致病性Th 17细胞分化中的T细胞内在作用。激活素A的表达在复发缓解型多发性硬化症患者和实验性自身免疫性脑脊髓炎小鼠中增加。用白细胞介素-6和激活素-A刺激诱导的分子程序反映了致病性Th 17细胞的分子程序，该分子程序通过阻断激活素-A信号传导而被抑制。T细胞中激活素A及其受体ALK 4的遗传破坏在体外和体内损害了致病性Th 17细胞分化。从机制上讲，ERK磷酸化是致病性Th 17细胞分化所必需的，TGF-β1-ALK 5而不是激活素-A-ALK 4信号转导抑制ERK磷酸化。因此，激活素A驱动致病性Th 17细胞分化，暗示激活素A-ALK 4-ERK轴作为Th 17细胞相关疾病的治疗靶点。鉴定控制致病性Th 17细胞的因素是至关重要的，因为它们在疾病和自身免疫中的作用。Wu等人证明T细胞内在激活素A信号传导，但与TGF-β1不密切相关，在自身免疫期间驱动致病性Th 17细胞分化和功能。这表明激活素-A是致病性Th-17介导的疾病的潜在治疗靶点。
Th17 cells are known to exert both pathogenic and non-pathogenic functions. While the cytokine TGF-β1 is instrumental to Th17 cell differentiation, it is dispensible for the generation of pathogenic-Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic-Th17 cell differentiation. Activin-A expression was increased in patients with relapsing-remitting multiple sclerosis, and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic-Th17 cells, which was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic-Th17 cell differentiation in vitro and in vivo. Mechanistically, ERK phosphorylation, which was essential for pathogenic-Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic-Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases. Identifying factors controlling pathogenic-Th17 cells is critical due to their roles in disease and autoimmunity. Wu et al. demonstrate T cell-intrinsic Activin-A signaling, but not closely related TGF-β1, drives pathogenic-Th17 cell differentiation and function during autoimmunity. This points to Activin-A as a potential therapeutic target in pathogenic Th-17-mediated diseases.
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