Exploiting the role of endogenous lymphoid-resident dendritic cells in the priming of NKT cells and CD8+ T cells to dendritic cell-based vaccines

PLoS One. 2011 Mar 31;6(3):e17657. doi: 10.1371/journal.pone.0017657.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Presenting Cells / cytology
  • Antigen-Presenting Cells / immunology
  • Antigens, Surface / genetics
  • Antigens, Surface / metabolism
  • Bone Marrow Cells / cytology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Dendritic Cells / cytology*
  • Dendritic Cells / immunology*
  • Flow Cytometry
  • Interferon-gamma / blood
  • Interleukin-12 / blood
  • Interleukin-4 / blood
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Lectins, C-Type / genetics
  • Lectins, C-Type / metabolism
  • Lymphoid Tissue / cytology*
  • Lymphoid Tissue / immunology
  • Mannose-Binding Lectins / genetics
  • Mannose-Binding Lectins / metabolism
  • Mice
  • Mice, Mutant Strains
  • Vaccines / immunology*

Substances

  • Antigens, Surface
  • Cd207 protein, mouse
  • Lectins, C-Type
  • Mannose-Binding Lectins
  • Vaccines
  • Interleukin-12
  • Interleukin-4
  • Interferon-gamma