Human CD141(+) Dendritic Cell and CD1c(+) Dendritic Cell Undergo Concordant Early Genetic Programming after Activation in Humanized Mice In Vivo
AuthorMinoda, Y; Virshup, I; Rojas, IL; Haigh, O; Wong, Y; Miles, JJ; Wells, CA; Radford, KJ
Source TitleFrontiers in Immunology
PublisherFRONTIERS MEDIA SA
University of Melbourne Author/sWells, Christine
AffiliationAnatomy and Neuroscience
Document TypeJournal Article
CitationsMinoda, Y., Virshup, I., Rojas, I. L., Haigh, O., Wong, Y., Miles, J. J., Wells, C. A. & Radford, K. J. (2017). Human CD141(+) Dendritic Cell and CD1c(+) Dendritic Cell Undergo Concordant Early Genetic Programming after Activation in Humanized Mice In Vivo. FRONTIERS IN IMMUNOLOGY, 8 (OCT), https://doi.org/10.3389/fimmu.2017.01419.
Access StatusOpen Access
Human immune cell subsets develop in immunodeficient mice following reconstitution with human CD34+ hematopoietic stem cells. These "humanized" mice are useful models to study human immunology and human-tropic infections, autoimmunity, and cancer. However, some human immune cell subsets are unable to fully develop or acquire full functional capacity due to a lack of cross-reactivity of many growth factors and cytokines between species. Conventional dendritic cells (cDCs) in mice are categorized into cDC1, which mediate T helper (Th)1 and CD8+ T cell responses, and cDC2, which mediate Th2 and Th17 responses. The likely human equivalents are CD141+ DC and CD1c+ DC subsets for mouse cDC1 and cDC2, respectively, but the extent of any interspecies differences is poorly characterized. Here, we exploit the fact that human CD141+ DC and CD1c+ DC develop in humanized mice, to further explore their equivalency in vivo. Global transcriptome analysis of CD141+ DC and CD1c+ DC isolated from humanized mice demonstrated that they closely resemble those in human blood. Activation of DC subsets in vivo, with the TLR3 ligand poly I:C, and the TLR7/8 ligand R848 revealed that a core panel of genes consistent with DC maturation status were upregulated by both subsets. R848 specifically upregulated genes associated with Th17 responses by CD1c+ DC, while poly I:C upregulated IFN-λ genes specifically by CD141+ DC. MYCL expression, known to be essential for CD8+ T cell priming by mouse DC, was specifically induced in CD141+ DC after activation. Concomitantly, CD141+ DC were superior to CD1c+ DC in their ability to prime naïve antigen-specific CD8+ T cells. Thus, CD141+ DC and CD1c+ DC share a similar activation profiles in vivo but also have induce unique signatures that support specialized roles in CD8+ T cell priming and Th17 responses, respectively. In combination, these data demonstrate that humanized mice provide an attractive and tractable model to study human DC in vitro and in vivo.
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