"Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig
"Alternatively activated" dendritic cells preferentially secrete IL-10, expand Foxp3+CD4+ T cells, and induce long-term organ allograft survival in combination with CTLA4-Ig
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DOI：
10.4049/jimmunol.177.9.5868
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发表时间：
2006-11-01
影响因子：
4.4
通讯作者：
Thomson, Angus W.
中科院分区：
文献类型：
--
作者：
Lan, Yuk Yuen;Wang, Zhiliang;Thomson, Angus W.
在这项研究中，我们从BALB/c（H2（d））小鼠骨髓祖细胞中增殖髓样树突状细胞（DC），IL-10和TGF-β，然后用LPS刺激细胞。这些“交替激活”（AA）DC表达较低的TLR 4转录比LPS刺激的对照DC和成熟的阻力。它们表达相对低水平的表面MHC II类、CD 40、CD 80、CD 86和程序性死亡配体2（137-DC; CD 273），而程序性死亡配体1（B7-H1; CD 274）和诱导型共刺激配体表达不受影响。与活化的对照DC相比，AADC分泌更高水平的IL-10，但分泌更低水平的IL-12 p70。他们的不良同种异体（C57 BL/10; B10）T细胞刺激活性和诱导同种异体抗原特异性，低反应性T细胞增殖的能力与增强的T细胞凋亡无关。在同种异体反应性T细胞群中诱导增加的IL-10产生，其中CD 4（+）Foxp 3（+）细胞扩增。与新鲜分离的调节性T细胞相比，AADC扩增的同种异体CD 4（+）CD 25（+）T细胞对T细胞增殖反应的抑制活性增强。AADC向次级淋巴组织的体内迁移未受损。BALB/c AADC单次输注到静止的B10受体诱导同种异体抗原特异性低反应性T细胞增殖并延长。随后心脏移植存活率。在AADC后第1天给予CTLA 4 -1g可显著增强该作用。移植物存活时间长（> 100天），移植物中浸润了CD 4（+）Foxp 3（+）细胞，移植物中的CD 4（+）T细胞可延长供体品系心脏在未处理受体中的存活时间。这些数据增强了对AADC调节特性的了解，并证明了其在血管化器官移植中的治疗潜力。
In this study, we propagated myeloid dendritic cells (DC) from BALB/c (H2(d)) mouse bone marrow progenitors in IL-10 and TGF-beta, then stimulated the cells with LPS. These "alternatively activated" (AA) DC expressed lower TLR4 transcripts than LPS-stimulated control DC and were resistant to maturation. They expressed comparatively low levels of surface MHC class II, CD40, CD80, CD86, and programmed death-ligand 2 (137-DC; CD273), whereas programmed death-ligand 1 (B7-H1; CD274) and inducible costimulatory ligand expression were unaffected. AADC secreted much higher levels of IL-10, but lower levels of IL-12p70 compared with activated control DC. Their poor allogeneic (C57BL/10; B10) T cell stimulatory activity and ability to induce alloantigen-specific, hyporesponsive T cell proliferation was not associated with enhanced T cell apoptosis. Increased IL-10 production was induced in the alloreactive T cell population, wherein CD4(+)Foxp3(+) cells were expanded. The AADC-expanded allogeneic CD4(+)CD25(+) T cells showed enhanced suppressive activity for T cell proliferative responses compared with freshly isolated T regulatory cells. In vivo migration of AADC to secondary lymphoid tissue was not impaired. A single infusion of BALB/c AADC to quiescent B10 recipients induced alloantigen-specific hyporesponsive T cell proliferation and prolonged. subsequent heart graft survival. This effect was potentiated markedly by CTLA4-1g, administered I day after the AADC. Transfer of CD4(+) T cells from recipients of long-surviving grafts (> 100 days) that were infiltrated with CD4(+)Foxp3(+) cells, prolonged the survival of donor-strain hearts in naive recipients. These data enhance insight into the regulatory properties of AADC and demonstrate their therapeutic potential in vascularized organ transplantation.