Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
VIB Center for Inflammation Research, Ghent, Belgium.
Allergy. 2020 Oct;75(10):2587-2598. doi: 10.1111/all.14334. Epub 2020 Jun 14.
Conventional type 1 dendritic cells (cDC1s) control anti-viral and anti-tumor immunity by inducing antigen-specific cytotoxic CD8 T-cell responses. Controversy exists whether cDC1s also control CD4 T helper 2 (Th2) cell responses, since suppressive and activating roles have been reported. DC activation status, controlled by the transcription factor NF-κB, might determine the precise outcome of Th-cell differentiation upon encounter with cDC1s. To investigate the role of activated cDC1s in Th2-driven immune responses, pulmonary cDC1s were activated by targeted deletion of A20/Tnfaip3, a negative regulator of NF-κB signaling.
To target pulmonary cDC1s, Cd207 (Langerin)-mediated excision of A20/Tnfaip3 was used, generating Tnfaip3 xCd207 (Tnfaip3 ) mice. Mice were exposed to house dust mite (HDM) to provoke Th2-mediated immune responses.
Mice harboring Tnfaip3-deficient cDC1s did not develop Th2-driven eosinophilic airway inflammation upon HDM exposure, but rather showed elevated numbers of IFNγ-expressing CD8 T cells. In addition, Tnfaip3 mice harbored increased numbers of IL-12-expressing cDC1s and elevated PD-L1 expression in all pulmonary DC subsets. Blocking either IL-12 or IFNγ in Tnfaip3 mice restored Th2 responses, whereas administration of recombinant IFNγ during HDM sensitization in C57Bl/6 mice blocked Th2 development.
These findings indicate that the activation status of cDC1s, shown by their specific expression of co-inhibitory molecules and cytokines, critically contributes to the development of Th2 cell-mediated disorders, most likely by influencing IFNγ production in CD8 T cells.
传统的 1 型树突状细胞（cDC1）通过诱导抗原特异性细胞毒性 CD8 T 细胞应答来控制抗病毒和抗肿瘤免疫。关于 cDC1 是否也控制 CD4 T 辅助 2（Th2）细胞应答存在争议，因为已经报道了抑制和激活作用。DC 激活状态受转录因子 NF-κB 控制，这可能决定 cDC1 与 Th 细胞相遇时 Th 细胞分化的确切结果。为了研究活化的 cDC1 在 Th2 驱动的免疫应答中的作用，通过靶向缺失 NF-κB 信号的负调节剂 A20/Tnfaip3 来激活肺 cDC1。
为了靶向肺 cDC1，使用 Cd207（朗格汉斯细胞）介导的 A20/Tnfaip3 缺失，生成 Tnfaip3 xCd207（Tnfaip3 ）小鼠。用屋尘螨（HDM）暴露小鼠以引发 Th2 介导的免疫应答。
在 HDM 暴露时，缺乏 Tnfaip3 的 cDC1 小鼠不会发展为 Th2 驱动的嗜酸性气道炎症，而是表现出 IFNγ 表达的 CD8 T 细胞数量增加。此外，Tnfaip3 小鼠具有更多的表达 IL-12 的 cDC1 和所有肺 DC 亚群中 PD-L1 表达的升高。在 Tnfaip3 小鼠中阻断 IL-12 或 IFNγ 恢复了 Th2 反应，而在 C57Bl/6 小鼠的 HDM 致敏期间给予重组 IFNγ 则阻止了 Th2 的发展。
这些发现表明，cDC1 的激活状态通过其特定的共抑制分子和细胞因子表达，极大地促进了 Th2 细胞介导的疾病的发展，这可能是通过影响 CD8 T 细胞中 IFNγ 的产生。
