Activation of human CD141 + and CD1c + dendritic cells in vivo with combined TLR3 and TLR7/8 ligation

Frances E Pearson, Karshing Chang, Yoshihito Minoda, Ingrid Marcela Leal Rojas, Oscar L Haigh, Ghazal Daraj, Kirsteen M Tullett, Kristen J Radford

Research output: Contribution to journalArticleResearchpeer-review

26 Citations (Scopus)

Abstract

Mice reconstituted with human hematopoietic stem cells are valuable models to study aspects of the human immune system in vivo. We describe a humanized mouse model (hu mice) in which fully functional human CD141 + and CD1c + myeloid and CD123 + plasmacytoid dendritic cells (DC) develop from human cord blood CD34 + cells in immunodeficient mice. CD141 + DC are the human equivalents of murine CD8 + /CD103 + DC which are essential for the induction of tumor-inhibitory cytotoxic T lymphocyte responses, making them attractive targets to exploit for the development of new cancer immunotherapies. We used CD34 + -engrafted NSG-A2 mice to investigate activation of DC subsets by synthetic dsRNA or ssRNA analogs polyinosinic-polycytidylic acid/poly I:C and Resiquimod/R848, agonists for TLR3 and TLR8, respectively, both of which are expressed by CD141 + DC. Injection of hu mice with these agonists resulted in upregulation of costimulatory molecules CD80, CD83 and CD86 by CD141 + and CD1c + DC alike, and their combination further enhanced expression of these molecules by both subsets. When combined, poly I:C and R848 enhanced serum levels of key cytokines associated with cross-presentation and the induction of cytotoxic T lymphocyte responses including IFN-α, IFN-β, IL-12 and CXCL10. These data advocate a combination of poly I:C and R848 TLR agonists as means of activating human DC for immunotherapy.

Original languageEnglish
Pages (from-to)390-400
Number of pages11
JournalImmunology and Cell Biology
Volume96
Issue number4
DOIs
Publication statusPublished - 1 Apr 2018
Externally publishedYes

Keywords

  • CD141 DC
  • CD1c DC
  • dendritic cell
  • humanized mouse
  • poly I:C
  • R848
  • TLR

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