The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells
The role of complement component 3 (C3) in differentiation of myeloid-derived suppressor cells
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DOI：
10.1182/blood-2012-06-440214
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发表时间：
2013-03-07
期刊：
影响因子：
20.3
通讯作者：
Lu, Lina
中科院分区：
文献类型：
--
作者：
Hsieh, Ching-Chuan;Chou, Hong-Shiue;Lu, Lina
髓系来源的抑制细胞(MDSCs)在免疫反应的调节中起着重要作用。MDSC的扩增在许多情况下都会发生，包括癌症、炎症、应激和移植耐受。小鼠的肝移植是自发接受的，但肝细胞移植被强烈排斥，这表明肝脏非实质细胞的免疫调节活性。我们已经报道，肝星状细胞(HPSCs)是肝脏中的基质细胞，具有极强的免疫抑制作用，可以通过诱导MDSCs有效地保护胰岛移植。本研究表明，在树突状细胞(DC)培养中加入hPSCs可促进MDSCs的发育，而不是高度依赖于hPSCs补体成分3(C3)的DC。C3(-/-)hPSCs失去了诱导MDSCs的能力，因此不能保护联合移植的胰岛移植物。HPSCs产生补体激活因子B和因子D，从而促进C3裂解为激活产物IC3b和C3d。在DC培养中加入外源性IC3b而不是C3d，可诱导分化出具有较强免疫抑制功能的MDSCs。这些发现为局部组织细胞介导的髓系细胞分化提供了新的机制见解，并可能有助于临床环境下基于MDSC的治疗的发展。
Myeloid-derived suppressor cells (MDSCs) play an important role in the regulation of the immune response. MDSC expansion occurs in many circumstances, including cancer, inflammation, stresses, and transplant tolerance. Liver transplants in mice are spontaneously accepted, but hepatocyte transplants are acutely rejected, suggesting the immunoregulatory activities of liver nonparenchymal cells. We have reported that hepatic stellate cells (HpSCs), the stromal cells in the liver, are immensely immunosuppressive and can effectively protect islet transplants via induction of MDSCs. The present study shows that the addition of HpSCs into dendritic cell (DC) culture promoted development of MDSCs, instead of DCs, which was highly dependent on complement component 3 (C3) from HpSCs. The C3(-/-) HpSCs lost their ability to induce MDSCs and, consequently, failed to protect the cotransplanted islet allografts. HpSCs produced complement activation factor B and factor D which then enhanced C3 cleavage to activation products iC3b and C3d. Addition of exogenous iC3b, but not C3d, into the DC culture led to the differentiation of MDSCs with potent immune-inhibitory function. These findings provide novel mechanistic insights into the differentiation of myeloid cells mediated by local tissue cells, and may assist in the development of MDSC-based therapy in clinical settings.