Angiopoietin 2 Stimulates TIE2-Expressing Monocytes To Suppress T Cell Activation and To Promote Regulatory T Cell Expansion

被引:162
作者
Coffelt, Seth B. [1 ]
Chen, Yung-Yi [1 ]
Muthana, Munitta [1 ]
Welford, Abigail F. [1 ]
Tal, Andrea O. [3 ]
Scholz, Alexander [3 ]
Plate, Karl H. [3 ]
Reiss, Yvonne [3 ]
Murdoch, Craig [2 ]
De Palma, Michele [4 ]
Lewis, Claire E. [1 ]
机构
[1] Univ Sheffield, Sch Med, Acad Unit Inflammat & Tumour Targeting, Sheffield S10 2RX, S Yorkshire, England
[2] Univ Sheffield, Acad Unit Oral & Maxillofacial Med & Surg, Sheffield S10 2RX, S Yorkshire, England
[3] Goethe Univ Frankfurt, Inst Neurol, Edinger Inst, Sch Med, D-60528 Frankfurt, Germany
[4] Ist Sci San Raffaele, Angiogenesis & Tumor Targeting Res Unit, San Raffaele Telethon Inst Gene Therapy, I-20132 Milan, Italy
关键词
GENE-EXPRESSION; MACROPHAGES; IL-10; IDENTIFICATION; RESPONSES; AUGMENTS; DELIVERY; PATHWAY; SYSTEM; BREAST;
D O I
10.4049/jimmunol.1002802
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Angiopoietin 2 (ANGPT2) is a proangiogenic cytokine whose expression is often upregulated by endothelial cells in tumors. Expression of its receptor, TIE2, defines a highly proangiogenic subpopulation of myeloid cells in circulation and tumors called TIE2-expressing monocytes/macrophages (TEMs). Genetic depletion of TEMs markedly reduces tumor angiogenesis in various tumor models, emphasizing their essential role in driving tumor progression. Previously, we demonstrated that ANGPT2 augments the expression of various proangiogenic genes, the potent immunosuppressive cytokine, IL-10, and a chemokine for regulatory T cells (Tregs), CCL17 by TEMs in vitro. We now show that TEMs also express higher levels of IL-10 than TIE2(-) macrophages in tumors and that ANGPT2-stimulated release of IL-10 by TEMs suppresses T cell proliferation, increases the ratio of CD4(+) T cells to CD8(+) T cells, and promotes the expansion of CD4(+)CD25(high)FOXP3(+) Tregs. Furthermore, syngeneic murine tumors expressing high levels of ANGPT2 contained not only high numbers of TEMs but also increased numbers of Tregs, whereas genetic depletion of tumor TEMs resulted in a marked reduction in the frequency of Tregs in tumors. Taken together, our data suggest that ANGPT2-stimulated TEMs represent a novel, potent immunosuppressive force in tumors. The Journal of Immunology, 2011, 186: 4183-4190.
引用
收藏
页码:4183 / 4190
页数:8
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