Tregs restrain dendritic cell autophagy to ameliorate autoimmunity
Tregs restrain dendritic cell autophagy to ameliorate autoimmunity
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DOI：
10.1172/jci92079
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发表时间：
2017-06-30
影响因子：
15.9
通讯作者：
Verginis, Panayotis
中科院分区：
文献类型：
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作者：
Alissafi, Themis;Banos, Aggelos;Verginis, Panayotis
事实证明，设计有效的基于 Treg 的疗法并建立自身免疫性疾病的临床耐受性具有挑战性。 Treg免疫疗法的临床实施受到与Treg的稳定性和分离程序以及Treg模式的特定体内靶点相关的各种障碍的阻碍。在此，我们证明 Foxp3(+) Tregs 通过以细胞毒性 T 淋巴细胞相关蛋白 4 依赖性（CTLA4 依赖性）方式抑制 DC 中的自噬机制，有效抑制体内自身免疫反应。自噬缺陷的 DC 表现出免疫原性潜力降低，并且无法启动自身抗原特异性 CD4(+) T 细胞来介导自身免疫。从机制上讲，CTLA4 结合促进了 DC 中 PI3K/Akt/mTOR 轴的激活和 FoxO1 核排除，导致自噬成分微管相关蛋白 1 轻链 3 beta (Lc3b) 的转录减少。 CTLA4-Ig（一种由 IgG1 的 Fc 区和 CTLA4 的胞外结构域组成的融合蛋白，也称为阿巴西普，商品名 Orencia）治疗的人类 DC 表现出自噬体形成水平降低，而来自 CTLA4-Ig 治疗的类风湿性关节炎患者的 DC 则显示出 LC3B 转录物减少。总的来说，我们的数据将 DC 中的经典自噬途径确定为 Foxp3(+) Treg 介导的抑制的分子靶标，从而改善自身免疫反应。这些发现可能为开发利用 Tregs 治疗自身免疫以及以耐受性紊乱为共同特征的疾病的治疗方案铺平道路。
Design of efficacious Treg-based therapies and establishment of clinical tolerance in autoimmune diseases have proven to be challenging. The clinical implementation of Treg immunotherapy has been hampered by various impediments related to the stability and isolation procedures of Tregs as well as the specific in vivo targets of Treg modalities. Herein, we have demonstrated that Foxp3(+) Tregs potently suppress autoimmune responses in vivo through inhibition of the autophagic machinery in DCs in a cytotoxic T-lymphocyte-associated protein 4-dependent (CTLA4-dependent) manner. Autophagy-deficient DCs exhibited reduced immunogenic potential and failed to prime autoantigen-specific CD4(+) T cells to mediate autoimmunity. Mechanistically, CTLA4 binding promoted activation of the PI3K/Akt/mTOR axis and FoxO1 nuclear exclusion in DCs, leading to decreased transcription of the autophagy component microtubule-associated protein 1 light chain 3 beta (Lc3b). Human DCs treated with CTLA4-Ig, a fusion protein composed of the Fc region of IgG1 and the extracellular domain of CTLA4 (also known as abatacept, marketed as Orencia), demonstrated reduced levels of autophagosome formation, while DCs from CTLA4-Ig-treated rheumatoid arthritis patients displayed diminished LC3B transcripts. Collectively, our data identify the canonical autophagy pathway in DCs as a molecular target of Foxp3(+) Treg-mediated suppression that leads to amelioration of autoimmune responses. These findings may pave the way for the development of therapeutic protocols that exploit Tregs for the treatment of autoimmunity as well as diseases in which disturbed tolerance is a common denominator.