P2X receptor agonist enhances tumor-specific CTL responses through CD70+ DC-mediated Th17 induction
P2X receptor agonist enhances tumor-specific CTL responses through CD70+ DC-mediated Th17 induction
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DOI：
10.1093/intimm/dxaa068
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发表时间：
2021-01-01
影响因子：
4.4
通讯作者：
Nakayama, Takashi
中科院分区：
文献类型：
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作者：
Yamamoto, Shinya;Matsuo, Kazuhiko;Nakayama, Takashi
已知细胞外 ATP 通过 P2X 受体 (P2XR) 刺激 CD70(+)CD11c(low) 树突状细胞 (DC)，从而促进肠固有层中的 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。这些发现促使我们测试 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（i）CD70（+）CD11c（低）DCs存在于鼻固有层中并表达P2X1R，P2X2R和P2X4R； (ii)从鼻固有层分离的CD70(+)CD11c(低)DC在αβ-ATP刺激下增强了共培养的脾CD4(+)T细胞的T(h)17细胞分化； (iii) 用卵清蛋白 (OVA) 和 αβ-ATP 进行鼻内免疫的小鼠，鼻固有层和区域淋巴结中的 OVA 特异性 T(h)17 细胞和 CTL 增加； (iv)与单独用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) 苏拉明是一种广泛的 P2 受体抑制剂，可抑制用 OVA 和 alpha beta-ATP 鼻内免疫的小鼠中 OVA 特异性 T(h)17 细胞和 CTL 的增加； (vi)苏拉明还消除了用OVA和针对E.G7-OVA的αβ-ATP鼻内免疫的小鼠增强的抗肿瘤免疫力。总的来说，αβ-ATP 可能是一种有前途的粘膜佐剂，它通过 CD70(+)CD11c(low) DC 介导的 T(h)17 诱导来促进抗原特异性 CTL 应答。
Extracellular ATP is known to promote T(h)17 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(h)17 cells enhance antitumor immunity by directly promoting proliferation of cytotoxic T lymphocytes (CTLs). These finding led us to test a P2XR agonist, alpha beta-methylene ATP (alpha beta-ATP), as a mucosal vaccine adjuvant to promote CTL responses through T(h)17 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(h)17 cell differentiation of cocultured splenic CD4(+) T cells upon stimulation with alpha beta-ATP; (iii) mice intranasally immunized with ovalbumin (OVA) and alpha beta-ATP had increased OVA-specific T(h)17 cells and CTLs in the nasal lamina propria and regional lymph nodes; (iv) mice intranasally immunized with OVA and alpha beta-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(h)17 cells and CTLs in mice intranasally immunized with OVA and alpha beta-ATP; and (vi) suramin also abrogated the enhanced antitumor immunity of mice intranasally immunized with OVA and alpha beta-ATP against E.G7-OVA. Collectively, alpha beta-ATP may be a promising mucosal adjuvant that promotes antigen-specific CTL responses via CD70(+)CD11c(low) DC-mediated T(h)17 induction.