Cyclic dinucleotides (CDNs), including cyclic di-GMP (CDG), are promising vaccine adjuvants in preclinical/clinical trials. The in vivo mechanisms of CDNs are not clear. Here we investigated the roles of lung DC subsets in promoting CDG mucosal adjuvant responses in vivo. Using genetically modified mice and adoptive cell transfer, we identified lung conventional DC 2 (cDC2) as the central player in CDG mucosal responses. We further identified two functionally distinct lung cDC2 subpopulations: TNFR2⁺pRelB⁺ and TNFR2^-pRelB^- cDC2. The TNFR2⁺ cDC2 were mature and migratory upon intranasal CDG administration while the TNFR2^- cDC2 were activated but not mature. Adoptive cell transfer showed that TNFR2^- cDC2 mediate the antibody responses of CDG, while the TNFR2⁺ cDC2 generate Th1/17 responses. Mechanistically, immature TNFR2^- cDC2 activate monocyte-derived DCs (moDCs), which do not take up intranasally administered CDG. moDCs promote CDG-induced generation of T follicular helper- and germinal center B cells in the lungs. Our data revealed a previously undescribed in vivo mode of DCs action, whereby an immature lung TNFR2^- cDC2 subpopulation directs the non-migratory moDCs to generate CDG mucosal responses in the lung.

中文翻译：

---

未成熟的肺 TNFR2-常规 DC 2 亚群激活 moDCs 以促进体内循环二 GMP 粘膜佐剂反应。

环状二核苷酸 (CDN)，包括环状二 GMP (CDG)，是临床前/临床试验中很有前途的疫苗佐剂。CDN 的体内机制尚不清楚。在这里，我们研究了肺 DC 亚群在体内促进 CDG 粘膜佐剂反应中的作用。使用转基因小鼠和过继细胞转移，我们将肺常规 DC 2 (cDC2) 确定为 CDG 粘膜反应的核心参与者。我们进一步确定了两个功能不同的肺 cDC2 亚群：TNFR2 ⁺ pRelB ⁺和 TNFR2 ^- pRelB ^- cDC2。TNFR2 ⁺ cDC2 在鼻内 CDG 给药后成熟并迁移，而 TNFR2 ^-cDC2 被激活但未成熟。过继细胞转移显示 TNFR2 ^- cDC2 介导 CDG 的抗体反应，而 TNFR2 ⁺ cDC2 产生 Th1/17 反应。从机制上讲，未成熟的 TNFR2 ^- cDC2 激活单核细胞衍生的 DCs (moDCs)，它不吸收鼻内给药的 CDG。moDCs 促进肺中 CDG 诱导的 T 滤泡辅助和生发中心 B 细胞的产生。我们的数据揭示了一种先前未描述的 DC 体内作用模式，即未成熟的肺 TNFR2 ^- cDC2 亚群指导非迁移性 moDC 在肺中产生 CDG 粘膜反应。