Institut Curie, PSL Research University, INSERM, U932, 26 rue d'Ulm, 75005, Paris, France.
Sanofi, Breakthrough Laboratory, 1 Impasse des Ateliers, 94400, Vitry-sur-Seine, France.
Nat Commun. 2018 Jul 2;9(1):2570. doi: 10.1038/s41467-018-04985-0.
Presentation of exogenous antigens on MHC-I molecules, termed cross-presentation, is essential for cytotoxic CD8 T cell responses. In mice, dendritic cells (DCs) that arise from monocytes (mo-DCs) during inflammation have a key function in these responses by cross-presenting antigens locally in peripheral tissues. Whether human naturally-occurring mo-DCs can cross-present is unknown. Here, we use human mo-DCs and macrophages directly purified from ascites to address this question. Single-cell RNA-seq data show that ascites CD1c DCs contain exclusively monocyte-derived cells. Both ascites mo-DCs and monocyte-derived macrophages cross-present efficiently, but are inefficient for transferring exogenous proteins into their cytosol. Inhibition of cysteine proteases, but not of proteasome, abolishes cross-presentation in these cells. We conclude that human monocyte-derived cells cross-present exclusively using a vacuolar pathway. Finally, only ascites mo-DCs provide co-stimulatory signals to induce effector cytotoxic CD8 T cells. Our findings thus provide important insights on how to harness cross-presentation for therapeutic purposes.
将外源性抗原呈递在 MHC-I 分子上，称为交叉呈递，对于细胞毒性 CD8 T 细胞反应至关重要。在小鼠中，炎症期间由单核细胞（mo-DC）产生的树突状细胞（DC）通过在周围组织中局部交叉呈递抗原在这些反应中具有关键作用。人类天然 mo-DC 是否可以交叉呈递抗原尚不清楚。在这里，我们使用直接从腹水分离的人类 mo-DC 和巨噬细胞来解决这个问题。单细胞 RNA-seq 数据表明，腹水 CD1c DC 仅包含单核细胞衍生的细胞。腹水 mo-DC 和单核细胞衍生的巨噬细胞都能有效地进行交叉呈递，但将外源性蛋白有效地转入其细胞质中却效率低下。抑制半胱氨酸蛋白酶，但不抑制蛋白酶体，可完全抑制这些细胞中的交叉呈递。我们得出结论，人类单核细胞衍生的细胞仅使用液泡途径进行交叉呈递。最后，只有腹水 mo-DC 提供共刺激信号来诱导效应细胞毒性 CD8 T 细胞。因此，我们的发现为如何利用交叉呈递来达到治疗目的提供了重要的见解。
