Abstract
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.
Highlights
Dendritic cells (DCs) are specialized antigen (Ag)-presenting cells that initiate and direct immune responses [1, 2]
Human CD141+ and CD1c+ DC subsets were found in all organs examined, with the largest numbers residing in the bone marrow (BM) compartment (Figure 1C)
We demonstrate that hu mice are a robust model to study human CD141+ DC and CD1c+ DC development and function in vivo
Summary
Dendritic cells (DCs) are specialized antigen (Ag)-presenting cells that initiate and direct immune responses [1, 2]. DC are a heterogenous cell population comprised of distinct subsets that harbor specialized capacity to drive specific immune responses. DC develop from CD34+ hematopoietic stem cells (HSC) in the bone marrow (BM) that develop into the common myeloid progenitor, giving rise to the more restricted macrophage/DC progenitor (MDP). The MDP can develop into monocytes, or the common DC progenitor (CDP). The CDP give rise to plasmacytoid (p) DC and two “classical” or “conventional” (c) DC subsets referred to as “cDC1” and “cDC2.”. PDCs are major producers of type-I IFN and are considered important for anti-viral immunity, the cDC1 and 2 subsets are critical for shaping adaptive immunity to intracellular and extracellular pathogens, respectively The CDP give rise to plasmacytoid (p) DC and two “classical” or “conventional” (c) DC subsets referred to as “cDC1” and “cDC2.” While surface marker expression has been the convention for characterization of conventional DC subsets, gene expression studies are redefining functional characteristics within these subsets [1, 3,4,5]. pDCs are major producers of type-I IFN and are considered important for anti-viral immunity, the cDC1 and 2 subsets are critical for shaping adaptive immunity to intracellular and extracellular pathogens, respectively
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