Development of an Inflammatory CD14+ Dendritic Cell Subset in Humanized Mice

• Main Authors: Ryutaro Iwabuchi, Keigo Ide, Kazutaka Terahara, Ryota Wagatsuma, Rieko Iwaki, Hiroko Matsunaga, Yasuko Tsunetsugu-Yokota, Haruko Takeyama, Yoshimasa Takahashi
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-03-01
• Series: Frontiers in Immunology
• Subjects: humanized mice; dendritic cell; DC3; CD14; inflammatory response; S100A8
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2021.643040/full

Humanized mouse models are attractive experimental models for analyzing the development and functions of human dendritic cells (DCs) in vivo. Although various types of DC subsets, including DC type 3 (DC3s), have been identified in humans, it remains unclear whether humanized mice can reproduce heterogeneous DC subsets. CD14, classically known as a monocyte/macrophage marker, is reported as an indicator of DC3s. We previously observed that some CD14+ myeloid cells expressed CD1c, a pan marker for bona fide conventional DC2 (cDC2s), in humanized mouse models in which human FLT3L and GM-CSF genes were transiently expressed using in vivo transfection (IVT). Here, we aimed to elucidate the identity of CD14+CD1c+ DC-like cells in humanized mouse models. We found that CD14+CD1c+ cells were phenotypically different from cDC2s; CD14+CD1c+ cells expressed CD163 but not CD5, whereas cDC2s expressed CD5 but not CD163. Furthermore, CD14+CD1c+ cells primed and polarized naïve CD4+ T cells toward IFN-γ+ Th1 cells more profoundly than cDC2s. Transcriptional analysis revealed that CD14+CD1c+ cells expressed several DC3-specific transcripts, such as CD163, S100A8, and S100A9, and were clearly segregated from cDC2s and monocytes. When lipopolysaccharide was administered to the humanized mice, the frequency of CD14+CD1c+ cells producing IL-6 and TNF-α was elevated, indicating a pro-inflammatory signature. Thus, humanized mice are able to sustain development of functional CD14+CD1c+ DCs, which are equivalent to DC3 subset observed in humans, and they could be useful for analyzing the development and function of DC3s in vivo.