Department of Pathology and Immunology, University of Geneva Medical School, Geneva, Switzerland.
NovImmune SA, Geneva, Switzerland.
Cancer Res. 2014 Nov 15;74(22):6430-40. doi: 10.1158/0008-5472.CAN-14-1149. Epub 2014 Sep 24.
Plasmacytoid dendritic cells (pDC) rapidly and massively produce type I IFN and other inflammatory cytokines in response to foreign nucleic acids, thereby indirectly influencing T-cell responses. Moreover, antigen (Ag)-presenting pDCs directly regulate T-cell differentiation. Depending on the immune environment, pDCs exhibit either tolerogenic or immunogenic properties. Here, we show that CpG-activated pDCs promote efficient Th17 differentiation. Indeed, Th17 responses are defective in mice selectively lacking MHCII on pDCs upon antigenic challenge. Importantly, in those mice, the frequency of Th17 cells infiltrating solid tumors is impaired. As a result, the recruitment of infiltrating leukocytes in tumors, including tumor-specific cytotoxic T lymphocytes (CTL), is altered and results in increased tumor growth. Importantly, following immunization with tumor Ag and CpG-B, MHCII-restricted Ag presentation by pDCs promotes the differentiation of antitumor Th17 cells that induce intratumor CTL recruitment and subsequent regression of established tumors. Our results highlight a new role for Ag presenting activated pDCs in promoting the development of Th17 cells and impacting on antitumor immunity.
浆细胞样树突状细胞（pDC）在受到外源核酸的刺激后，会迅速大量地产生 I 型干扰素和其他炎症细胞因子，从而间接影响 T 细胞的反应。此外，抗原呈递 pDC 还可以直接调节 T 细胞的分化。pDC 根据免疫环境的不同，表现出耐受性或免疫原性的特性。在这里，我们发现 CpG 激活的 pDC 可以促进 Th17 细胞的有效分化。实际上，在抗原刺激下，特异性缺失 pDC 上 MHCII 的小鼠的 Th17 反应会出现缺陷。重要的是，在这些小鼠中，浸润实体瘤的 Th17 细胞的频率受损。结果，肿瘤内浸润白细胞的募集，包括肿瘤特异性细胞毒性 T 淋巴细胞（CTL），发生改变，导致肿瘤生长增加。重要的是，在用肿瘤抗原和 CpG-B 进行免疫接种后，pDC 上 MHCII 限制的抗原呈递促进了抗肿瘤 Th17 细胞的分化，诱导肿瘤内 CTL 的募集，并随后导致已建立的肿瘤消退。我们的研究结果强调了活化的抗原呈递 pDC 在促进 Th17 细胞的发育和影响抗肿瘤免疫中的新作用。
