MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF
MFG-E8-mediated uptake of apoptotic cells by APCs links the pro- and antiinflammatory activities of GM-CSF
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DOI：
10.1172/jci30966
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Dranoff, Glenn
中科院分区：
文献类型：
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作者：
Jinushi, Masahisa;Nakazaki, Yukoh;Dranoff, Glenn
粒细胞-巨噬细胞集落刺激因子（GM-CSF）增强对肿瘤和感染的保护，但GM-CSF缺陷小鼠会发生炎症性疾病。在这里，我们表明，GM-CSF是所需的抗原呈递细胞中的乳脂球EGF 8（MFG-E8）的表达，MFG-E8介导的摄取凋亡细胞是GM-CSF触发的耐受性和免疫力的关键决定因素。在暴露于凋亡细胞后，GM-CSF缺陷型抗原呈递细胞（APC）产生改变的细胞因子谱，导致T细胞减少和Th 1细胞增加，而IFN-γ的同时消融促进Th 17细胞。在野生型小鼠中，MFG-E8通过Treg诱导减弱分泌GM-CSF的肿瘤细胞的疫苗接种活性，而显性阴性MFG-E8突变体通过Treg抑制增强GM-CSF刺激的肿瘤破坏。这些发现阐明了凋亡细胞的免疫调节作用，并提出了调节癌症和自身免疫中CD 4（+）T细胞亚群的新治疗策略。
Granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances protection against tumors and infections, but GM-CSF-deficient mice develop inflammatory disease. Here we show that GM-CSF is required for the expression of milk fat globule EGF 8 (MFG-E8) in antigen-presenting cells, and that MFG-E8-mediated uptake of apoptotic cells is a key determinant of GM-CSF-triggered tolerance and immunity. Upon exposure to apoptotic cells, GM-CSF-deficient antigen-presenting cells (APCs) produce an altered cytokine profile that results in decreased Tregs and increased Th1 cells, whereas concurrent ablation of IFN-gamma promotes Th17 cells. In wild-type mice, MFG-E8 attenuates the vaccination activity of GM-CSF-secreting tumor cells through Treg induction, whereas a dominant-negative MFG-E8 mutant potentiates GM-CSF-stimulated tumor destruction through Treg inhibition. These findings clarify the immunoregulatory effects of apoptotic cells and suggest new therapeutic strategies to modulate CD4(+) T cell subsets in cancer and autoimmunity.