Journal
BLOOD
Volume 121, Issue 25, Pages 5034-5044Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2012-12-473413
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Funding
- National Cancer Institute [R01CA108609]
- Sassella Foundation [10/02, 11/02, 12/02]
- Cancer Research Switzerland [KFS-02652-08-2010]
- Association for International Cancer Research [11-0516]
- KFSPMS of the University of Zurich
- KFSPHLD of the University of Zurich
- Vontobel Foundation
- Baugarten Foundation
- EMDO Foundation
- Sobek Foundation
- Fondation Acteria
- Novartis
- Swiss National Science Foundation [310030_143979, CRSII3_136241]
- University of Zurich
- Croucher Foundation Hong Kong
- Worldwide Cancer Research [11-0516] Funding Source: researchfish
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Functional differences between human dendritic cell (DC) subsets and the potential benefits of targeting them with vaccines remain poorly defined. Here we describe that mice with reconstituted human immune system components (huNSG mice) develop all human conventional and plasmacytoid DC compartments in lymphoid organs. Testing different Toll-like receptor agonists for DC maturation in vivo, we found that IL-12p70 and interferon (IFN)-alpha production correlated with the maturation of CD141(+) (BDCA3(+)) conventional DCs in huNSG mice. Furthermore, depletion of CD141(+) DCs before stimulation significantly reduced IFN-alpha levels in vivo. This DC subset produced similar total amounts but different subtypes of IFN-alpha in response to synthetic double-stranded RNA compared with plasmacytoid DCs in response to a single-stranded RNA equivalent. Moreover, synthetic double-stranded RNA as adjuvant and antigen targeting to the endocytic receptor DEC-205, a combination that focuses antigen presentation for T-cell priming on CD141(+) DCs, stimulated antigen-specific human CD4(+) T-cell responses. Thus, the human CD141(+) DC subset is a prominent source of IFN-alpha and interleukin-12 production and should be further evaluated for vaccine development.
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