Human CD141(+) dendritic cell and CD1c(+) dendritic cell undergo concordant early genetic programming after activation in humanized mice in vivo

Minoda, Yoshihito, Virshup, Isaac, Rojas, Ingrid Leal, Haigh, Oscar, Wong, Yide, Miles, John J., Wells, Christine A., and Radford, Kristen 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.

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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-lambda 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 naive 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.

Item ID: 51623
Item Type: Article (Research - C1)
ISSN: 1664-3224
Keywords: humanized mice, dendritic cells, CD141(+) DC, CD1c(+) DC, poly I:C, R848, microarray
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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Date Deposited: 22 Nov 2017 07:53
FoR Codes: 11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110799 Immunology not elsewhere classified @ 100%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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