Centenary Institute, Newtown, NSW, Australia.
Sydney Medical School, University of Sydney, Camperdown, NSW, Australia.
Immunol Cell Biol. 2018 Nov;96(10):1131-1139. doi: 10.1111/imcb.12186. Epub 2018 Jul 20.
Conventional dendritic cells (cDCs) are continuously replenished by bone marrow-derived precursors called pre-DCs, which traffic through the blood to peripheral tissues. Pre-DCs are a heterogeneous population that includes cDC subset-committed progenitors, namely pre-cDC1 and pre-cDC2, which give rise to mature cDC1 and cDC2, respectively. Regulation of pre-DC subset trafficking is thought to aid the host response to immune challenge. However, the molecular cues regulating pre-cDC1 versus pre-cDC2 trafficking toward peripheral sites during homeostasis and disease remain elusive. Here, we report that pre-cDC1 but not pre-cDC2 express the T helper type 1-associated chemokine receptor CXCR3. Moreover, we identify a cell-intrinsic role for CXCR3 in the trafficking of pre-cDC1 to melanoma tumors but not to non-inflamed organs. We also show that tumor cDC1 numbers can be increased pharmacologically by targeting dipeptidyl peptidase-4 (CD26), a negative regulator of CXCR3 ligands. Our findings demonstrate that pre-cDC1 trafficking is regulated distinctly from pre-cDC2, which is relevant for our understanding of the DC lineage in the context of cancer and inflammation.
传统树突状细胞 (cDCs) 由骨髓衍生的前体细胞 (称为 pre-DC) 不断补充，这些前体细胞通过血液流向外周组织。Pre-DC 是一个异质性群体，包括 cDC 亚群定向祖细胞，即 pre-cDC1 和 pre-cDC2，它们分别产生成熟的 cDC1 和 cDC2。Pre-DC 亚群迁移的调节被认为有助于宿主对免疫挑战的反应。然而，在稳态和疾病期间调节 pre-cDC1 与 pre-cDC2 向周围部位迁移的分子线索仍然难以捉摸。在这里，我们报告 pre-cDC1 而不是 pre-cDC2 表达辅助性 T 细胞 1 相关趋化因子受体 CXCR3。此外，我们确定了 CXCR3 在 pre-cDC1 向黑色素瘤肿瘤而不是非炎症器官迁移中的细胞内在作用。我们还表明，通过靶向二肽基肽酶-4 (CD26)（CXCR3 配体的负调节剂）可以在药理学上增加肿瘤 cDC1 的数量。我们的研究结果表明，pre-cDC1 的迁移受到不同于 pre-cDC2 的调节，这对于我们在癌症和炎症背景下理解 DC 谱系具有重要意义。
