In Vivo-Generated Antigen-Specific Regulatory T Cells Treat Autoimmunity Without Compromising Antibacterial Immune Response
In Vivo-Generated Antigen-Specific Regulatory T Cells Treat Autoimmunity Without Compromising Antibacterial Immune Response
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DOI：
10.1126/scitranslmed.3008895
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发表时间：
2014-06-18
影响因子：
17.1
通讯作者：
Chen, WanJun
中科院分区：
文献类型：
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作者：
Kasagi, Shimpei;Zhang, Pin;Chen, WanJun
利用调节性 T (T-reg) 细胞是治疗自身免疫性疾病的一种有前景的方法。然而，在不损害有益免疫反应的情况下诱导靶向炎症免疫细胞的抗原特异性T-reg细胞仍然是一个尚未解决的挑战。我们开发了一种在体内产生自身抗原特异性 T-reg 细胞的途径，该途径对小鼠实验性自身免疫性脑脊髓炎和非肥胖糖尿病具有治疗作用。具体来说，我们通过全身亚致死辐射或用特异性抗体耗尽 B 和 CD8(+) T 细胞来诱导免疫细胞凋亡，然后对患有自身免疫性疾病的小鼠施用自身抗原肽。我们从机制上证明，凋亡细胞触发专职吞噬细胞产生转化生长因子-β，在此过程中，自身抗原肽引导幼稚CD4(+) T细胞在体内分化为Foxp3(+) T-reg细胞，而不是分化为效应T细胞。这些抗原特异性 Treg 细胞可以特异性改善自身免疫，而不会影响对细菌抗原的免疫反应。因此，我们成功地产生了具有自身免疫治疗活性的抗原特异性T-reg细胞。这些发现可能会促进针对多发性硬化症和 1 型糖尿病以及其他自身免疫性疾病的抗原特异性 T-reg 细胞介导的免疫疗法的开发。
Harnessing regulatory T (T-reg) cells is a promising approach for treating autoimmune disease. However, inducing antigen-specific T-reg cells that target inflammatory immune cells without compromising beneficial immune responses has remained an unmet challenge. We developed a pathway to generate autoantigen-specific T-reg cells in vivo, which showed therapeutic effects on experimental autoimmune encephalomyelitis and nonobese diabetes in mice. Specifically, we induced apoptosis of immune cells by systemic sublethal irradiation or depleted B and CD8(+) T cells with specific antibodies and then administered autoantigenic peptides in mice with established autoimmune diseases. We demonstrated mechanistically that apoptotic cells triggered professional phagocytes to produce transforming growth factor-beta, under which the autoantigenic peptides directed naive CD4(+) T cells to differentiate into Foxp3(+) T-reg cells instead of into T effector cells in vivo. These antigen-specific Treg cells specifically ameliorated autoimmunity without compromising immune responses to bacterial antigen. We have thus successfully generated antigen-specific T-reg cells with therapeutic activity toward autoimmunity. The findings may lead to the development of antigen-specific T-reg cell-mediated immunotherapy for multiple sclerosis and type 1 diabetes and also other autoimmune diseases.