Abstract

Extracellular ATP is known to promote T_h17 cell differentiation in the intestinal lamina propria by stimulating CD70⁺CD11c^low dendritic cells (DCs) via P2X receptors (P2XRs). Recent studies have also shown that T_h17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, αβ-methylene ATP (αβ-ATP), as a mucosal vaccine adjuvant to promote CTL responses through T_h17 induction. We demonstrated that (i) CD70⁺CD11c^low DCs were present in the nasal lamina propria and expressed P2X1R, P2X2R and P2X4R; (ii) CD70⁺CD11c^low DCs isolated from the nasal lamina propria enhanced T_h17 cell differentiation of cocultured splenic CD4⁺ T cells upon stimulation with αβ-ATP; (iii) mice intranasally immunized with ovalbumin (OVA) and αβ-ATP had increased OVA-specific T_h17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (iv) mice intranasally immunized with OVA and αβ-ATP also had elevated resistance to E.G7-OVA tumor growth compared with those intranasally immunized with OVA alone; (v) suramin, a broad-range inhibitor of P2 receptors, suppressed the increases of OVA-specific T_h17 cells and CTLs in mice intranasally immunized with OVA and αβ-ATP; and (vi) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and αβ-ATP against E.G7-OVA. Collectively, αβ-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70⁺CD11c^low DC-mediated T_h17 induction.

中文翻译：

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P2X 受体激动剂通过 CD70+ DC 介导的 Th17 诱导增强肿瘤特异性 CTL 反应

摘要

已知细胞外 ATP通过 P2X 受体 (P2XR) 刺激 CD70 ⁺ CD11c^低树突状细胞 (DC) 来促进肠固有层中的T _{h 17 细胞分化。}最近的研究还表明，T _h 17 细胞通过直接促进细胞毒性 T 淋巴细胞 (CTL) 的增殖来增强抗肿瘤免疫。这些发现使我们测试了 P2XR 激动剂 αβ-亚甲基 ATP (αβ-ATP) 作为粘膜疫苗佐剂通过 T _h 17 诱导促进 CTL 反应。我们证明了 (i) CD70 ⁺ CD11c^低DCs 存在于鼻固有层中并表达 P2X1R、P2X2R 和 P2X4R；(ii) CD70 ⁺ CD11c^低用 αβ-ATP 刺激后，从鼻固有层分离的 DC 增强了共培养的脾 CD4 ^{+ T 细胞的 T} _{h 17 细胞分化；}(iii) 用卵清蛋白 (OVA) 和 αβ-ATP 鼻内免疫的小鼠在鼻固有层和区域淋巴结中增加了 OVA 特异性 T _{h 17 细胞和 CTL；}(iv) 与仅用 OVA 鼻内免疫的小鼠相比，用 OVA 和 αβ-ATP 鼻内免疫的小鼠对 E.G7-OVA 肿瘤生长的抵抗力也有所提高；(v) 苏拉明，一种广泛的 P2 受体抑制剂，抑制 OVA 特异性 T _h的增加OVA和αβ-ATP鼻内免疫小鼠的17个细胞和CTL；(vi) 苏拉明还消除了用 OVA 和 αβ-ATP 对 E.G7-OVA 进行鼻内免疫的小鼠增强的抗肿瘤免疫力。^{总的来说，αβ-ATP 可能是一种很有前途的粘膜佐剂，它通过 CD70 +} CD11c^低DC 介导的 T _h 17 诱导来促进抗原特异性 CTL 反应。