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天然 CD8⁺25⁺调节性 T 细胞分泌的外泌体能够抑制细胞毒性 T 淋巴细胞介导的针对 B16 黑色素瘤的免疫反应。

Natural CD8⁺25⁺ regulatory T cell-secreted exosomes capable of suppressing cytotoxic T lymphocyte-mediated immunity against B16 melanoma.

机构信息

Cancer Research Unit, Saskatchewan Cancer Agency, Division of Oncology, University of Saskatchewan, Saskatoon, Saskatchewan S7N 4H4, Canada.

出版信息

Biochem Biophys Res Commun. 2013 Aug 16;438(1):152-5. doi: 10.1016/j.bbrc.2013.07.044. Epub 2013 Jul 20.

Abstract

Natural CD4(+)25(+) and CD8(+)25(+) regulatory T (Tr) cells have been shown to inhibit autoimmune diseases. Immune cells secrete exosomes (EXOs), which are crucial for immune regulation. However, immunomodulatory effect of natural Tr cell-secreted EXOs is unknown. In this study, we purified natural CD8(+)25(+) Tr cells from C57BL/6 mouse naive CD8(+) T cells, and in vitro amplified them with CD3/CD28 beads. EXOs (EXO(Tr)) were purified from Tr cell's culture supernatants by differential ultracentrifugation and analyzed by electron microscopy, Western blot and flow cytometry. Our data showed that EXO(Tr) had a "saucer" or round shape with 50-100 nm in diameter, contained EXO-associated markers LAMP-1 and CD9, and expressed natural Tr cell markers CD25 and GITR. To assess immunomodulatory effect, we i.v. immunized C57BL/6 mice with ovalbumin (OVA)-pulsed DCs (DC(OVA)) plus Tr cells or EXO(Tr), and then assessed OVA-specific CD8(+) T cell responses using PE-H-2K(b)/OVA tetramer and FITC-anti-CD8 antibody staining by flow cytometry and antitumor immunity in immunized mice with challenge of OVA-expressing BL6-10OVA melanoma cells. We demonstrated that DC(OVA)-stimulated CD8(+) T cell responses and protective antitumor immunity significantly dropped from 2.52% to 1.08% and 1.81% (p<0.05), and from 8/8 to 2/8 and 5/8 mice DC(OVA) (p<0.05) in immunized mice with co-injection of Tr cells and EXO(Tr), respectively. Our results indicate that natural CD8(+)25(+) Tr cell-released EXOs, alike CD8(+)25(+) Tr cells, can inhibit CD8(+) T cell responses and antitumor immunity. Therefore, EXOs derived from natural CD4(+)25(+) and CD8(+)25(+) Tr cells may become an alternative for immunotherapy of autoimmune diseases.

摘要

天然的 CD4(+)25(+)和 CD8(+)25(+)调节性 T(Tr)细胞已被证明可以抑制自身免疫性疾病。免疫细胞分泌外泌体(EXOs),这对于免疫调节至关重要。然而,天然 Tr 细胞分泌的 EXOs 的免疫调节作用尚不清楚。在这项研究中,我们从 C57BL/6 小鼠幼稚 CD8(+)T 细胞中纯化了天然的 CD8(+)25(+)Tr 细胞,并通过 CD3/CD28 珠粒在体外扩增它们。通过差速超速离心从 Tr 细胞的培养上清液中纯化外泌体(EXO(Tr)),并通过电子显微镜、Western blot 和流式细胞术进行分析。我们的数据显示,EXO(Tr)呈“碟形”或圆形,直径为 50-100nm,含有外泌体相关标记物 LAMP-1 和 CD9,并表达天然 Tr 细胞标记物 CD25 和 GITR。为了评估免疫调节作用,我们通过静脉注射用卵清蛋白(OVA)脉冲的树突状细胞(DC(OVA))加 Tr 细胞或 EXO(Tr)免疫 C57BL/6 小鼠,然后通过流式细胞术使用 PE-H-2K(b)/OVA 四聚体和 FITC-抗-CD8 抗体染色评估 OVA 特异性 CD8(+)T 细胞反应,并在免疫接种的小鼠中用表达 OVA 的 BL6-10OVA 黑色素瘤细胞进行挑战,评估抗肿瘤免疫。我们证明,DC(OVA)刺激的 CD8(+)T 细胞反应和保护性抗肿瘤免疫显著下降,从 2.52%降至 1.08%和 1.81%(p<0.05),从 8/8 降至 2/8 和 5/8 只小鼠(p<0.05),在共注射 Tr 细胞和 EXO(Tr)的免疫小鼠中。我们的结果表明,天然的 CD8(+)25(+)Tr 细胞释放的 EXOs,与 CD8(+)25(+)Tr 细胞一样,可以抑制 CD8(+)T 细胞反应和抗肿瘤免疫。因此,天然的 CD4(+)25(+)和 CD8(+)25(+)Tr 细胞衍生的 EXOs 可能成为自身免疫性疾病免疫治疗的一种替代方法。

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