Enhanced activation of human CD141+ DC and CD1c+ DC in vivo with combined TLR3/TLR8 ligation: implications for DC-based immunotherapy
Karshing Chang, Frances E. Pearson, Yoshihito Minoda, Ingrid M. Leal Rojas, Kirsteen Tullett, Kristen J. Radford*
Cancer Immunotherapies Group, Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland. Australia.
Mice reconstituted with human hematopoietic stem cells (humanised mice) are a practical model to study aspects of the human immune system. We developed a humanised mouse model in which fully functional human DC subsets, including CD141+ and CD1c+ DC and plasmacytoid DC, develop from human CD34+ cord blood progenitor cells in immunodeficient mice1. CD141+ DC are the human equivalents of the mouse CD8+ DC that are essential for the induction of cytotoxic T lymphocyte responses against cancers and many pathogens, making them attractive targets to exploit for the development of new vaccines2. We used humanised mice to investigate activation of CD141+ DC by poly I:C and R848, agonists for TLR3 and TLR8 respectively, which are both expressed by CD141+ DC. Activation with either poly I:C or R848 upregulated costimulatory molecules CD40, CD80, CD83 and CD86 by CD141+ DC and CD1c+ DC to a similar extent in vivo and the combination of poly I:C and R848 further enhanced costimulatory molecule expression by both subsets. Poly I:C and R848 combined resulted in higher levels of IFN-λ and IL-12 in the serum compared to either agonist alone. These data suggest that poly I:C and R848 combined is an effective adjuvant for CD141+ DC.
References: 1Ding et al (2014) J Immunol, 192(4):1982-9. 2Hildner et al (2008) Science, 332(5904): 1097-100
Funding: Worldwide Cancer Research, United States Department of Defense, Australian National Health and Medical Research Council