期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 9, 页码 1191-1204出版社
WILEY
DOI: 10.15252/emmm.201303283
关键词
CD8(+); T-cell responses; dendritic cells; Langerhans cells; skin; tolerance
资金
- COMET Center ONCOTYROL (Project Cell Therapy Unit) - Austrian Federal Ministry for Transport, Innovation and Technology (via the Austrian Research Promotion Agency) [2.3.1]
- Standortagentur Tirol
- Austrian Science Fund [FWF-P21487, FWF-W1101]
- NIH/NIAMS [1K99AR062595]
- Centre National pour la Recherche Scientifique
- Agence Nationale pour la Recherche (Program 'Investissements d'Avenir') [ANR-11-EQPX-022]
- Austrian Science Fund (FWF) [P21487] Funding Source: Austrian Science Fund (FWF)
- Austrian Science Fund (FWF) [P 21487] Funding Source: researchfish
Skin dendritic cells (DCs) control the immunogenicity of cutaneously administered vaccines. Antigens targeted to DCs via the C-type lectin Langerin/CD207 are cross-presented to CD8(+) T cells in vivo. We investigated the relative roles of Langerhans cells (LCs) and Langerin(+) dermal DCs (dDCs) in different vaccination settings. Poly(I:C) and anti-CD40 agonist antibody promoted cytotoxic responses upon intradermal immunization with ovalbumin (OVA)-coupled anti-Langerin antibodies (Langerin/OVA). This correlated with CD70 upregulation in Langerin(+) dDCs, but not LCs. In chimeric mice where Langerin targeting was restricted to dDCs, CD8(+) T-cell memory was enhanced. Conversely, providing Langerin/OVA exclusively to LCs failed to prime cytotoxicity, despite initial antigen cross-presentation to CD8(+) T cells. Langerin/OVA combined with imiquimod could not prime CD8(+) T cells and resulted in poor cytotoxicity in subsequent responses. This tolerance induction required targeting and maturation of LCs. Altogether, Langerin(+) dDCs prime long-lasting cytotoxic responses, while cross-presentation by LCs negatively influences CD8(+) T-cell priming. Moreover, this highlights that DCs exposed to TLR agonists can still induce tolerance and supports the existence of qualitatively different DC maturation programs.
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