title: Exploiting the role of endogenous lymphoid-resident dendritic cells in the priming of NKT cells and CD8+ T cells to dendritic cell-based vaccines.
abstract: Transfer of antigen between antigen-presenting cells (APCs) is potentially a physiologically relevant mechanism to spread antigen to cells with specialized stimulatory functions. Here we show that specific CD8+ T cell responses induced in response to intravenous administration of antigen-loaded bone marrow-derived dendritic cells (BM-DCs), were ablated in mice selectively depleted of endogenous lymphoid-resident langerin+ CD8α+ dendritic cells (DCs), suggesting that the antigen is transferred from the injected cells to resident APCs. In contrast, antigen-specific CD4+ T cells were primed predominantly by the injected BM-DCs, with only very weak contribution of resident APCs. Crucially, resident langerin+ CD8α+ DCs only contributed to the priming of CD8+ T cells in the presence of maturation stimuli such as intravenous injection of TLR ligands, or by loading the BM-DCs with the glycolipid α-galactosylceramide (α-GalCer) to recruit the adjuvant activity of activated invariant natural killer-like T (iNKT) cells. In fact, injection of α-GalCer-loaded CD1d-/- BM-DCs resulted in potent iNKT cell activation, suggesting that this glycolipid antigen can also be transferred to resident CD1d+ APCs. While iNKT cell activation per se was independent of langerin+ CD8α+ DCs, some iNKT cell-mediated activities were reduced, notably release of IL-12p70 and transactivation of NK cells. We conclude that both protein and glycolipid antigens can be exchanged between distinct DC species. These data suggest that the efficacy of DC-based vaccination strategies may be improved by the incorporation of a systemic maturation signal aimed to engage resident APCs in CD8+ T cell priming, and α-GalCer may be particularly well suited to this purpose.
authors.affiliation: Malaghan Institute of Medical Research, Wellington, New Zealand. tpetersen@malaghan.org.nz
authors.forename: Troels R
authors.initials: TR
authors.lastname: Petersen
authors.forename: Dianne
authors.initials: D
authors.lastname: Sika-Paotonu
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Knight
authors.forename: Helen M A
authors.initials: HM
authors.lastname: Simkins
authors.forename: Ian F
authors.initials: IF
authors.lastname: Hermans
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology*; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D015847:Interleukin-4 / Q000097:blood; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008221:Lymphoid Tissue / Q000166:cytology* / Q000276:immunology; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D014612:Vaccines / Q000276:immunology*
chemical_list: D000954:Antigens, Surface; C498497:Cd207 protein, mouse; D037181:Lectins, C-Type; D037241:Mannose-Binding Lectins; D014612:Vaccines; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma