CD3-specific antibody-induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells
CD3-specific antibody-induced immune tolerance involves transforming growth factor-β from phagocytes digesting apoptotic T cells
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DOI：
10.1038/nm1749
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发表时间：
2008-05-01
期刊：
影响因子：
82.9
通讯作者：
Chen, WanJun
中科院分区：
文献类型：
--
作者：
Perruche, Sylvain;Zhang, Pin;Chen, WanJun
完整的CD3特异性抗体可瞬间耗尽大量T细胞，继而诱导长期免疫耐受。然而，系统性耐受的潜在机制仍不清楚。我们在这里表明，对CD3抗体完整的正常小鼠的治疗增加了暴露于凋亡T细胞的吞噬细胞产生的系统性转化生长因子-β(TGF-β)。巨噬细胞和未成熟树突状细胞(IDCs)中，巨噬细胞和未成熟树突状细胞(IDCs)摄取凋亡的T细胞后分泌转化生长因子-β，在培养中诱导CD4(+)Foxp3(+)调节性T细胞，并在体内由CD3特异性抗体介导的免疫耐受。根据这些结果，去除巨噬细胞和IDCs不仅取消了CD3特异性抗体介导的预防髓鞘少突胶质细胞糖蛋白诱导的急性实验性自身免疫性脑脊髓炎(EAE)的作用，而且逆转了CD3抗体对复发缓解型EAE模型的治疗作用。因此，CD3特异性抗体诱导的免疫耐受与吞噬细胞中产生的转化生长因子-β有关，这表明细胞凋亡与主动抑制免疫耐受有关。
Intact CD3-specific antibody transiently depletes large numbers of T cells and subsequently induces long-term immune tolerance. The underlying mechanisms for the systemic tolerance, however, remain unclear. We show here that treatment of normal mice with intact antibody to CD3 increases systemic transforming growth factor-beta ( TGF-beta) produced by phagocytes exposed to apoptotic T cells. Among the phagocytes, macrophages and immature dendritic cells (iDCs) secrete TGF-beta upon ingestion of apoptotic T cells, which induces CD4(+)Foxp3(+) regulatory T cells in culture and contributes to immune tolerance mediated by CD3-specific antibody in vivo. In accordance with these results, depletion of macrophages and iDCs not only abrogates CD3-specific antibody-mediated prevention of myelin oligodendrocyte glycoprotein-induced acute experimental autoimmune encephalomyelitis ( EAE), but also reverses the therapeutic effects of antibody to CD3 on established disease in a model of relapsing-remitting EAE. Thus, CD3-specific antibody-induced immune tolerance is associated with TGF-beta production in phagocytes involved in clearing apoptotic T cells, which suggests that apoptosis is linked to active suppression in immune tolerance.