Dendritic cell preactivation impairs MHC class II presentation of vaccines and endogenous viral antigens.
When dendritic cells (DCs) encounter signals associated with infection or inflammation, they become activated and undergo maturation. Mature DCs are very efficient at presenting antigens captured in association with their activating signal but fail to present subsequently encountered antigens, at least in vitro. Such impairment of MHC class II (MHC II) antigen presentation has generally been thought to be a consequence of down-regulation of endocytosis, so it might be expected that antigens synthesized by the DCs themselves (for instance, viral antigens) would still be presented by mature DCs. Here, we show that DCs matured in vivo could still capture and process soluble antigens, but were unable to present peptides derived from these antigens. Furthermore, presentation of viral antigens synthesized by the DCs themselves was also severely impaired. Indeed, i.v. injection of pathogen mimics, which caused systemic DC activation in vivo, impaired the induction of CD4 T cell responses against subsequently encountered protein antigens. This immunosuppressed state could be reversed by adoptive transfer of DCs loaded exogenously with antigens, demonstrating that impairment of CD4 T cell responses was due to lack of antigen presentation rather than to overt suppression of T cell activation. The biochemical mechanism underlying this phenomenon was the down-regulation of MHC II-peptide complex formation that accompanied DC maturation. These observations have important implications for the design of prophylactic and therapeutic DC vaccines and contribute to the understanding of the mechanisms causing immunosuppression during systemic blood infections.
Young
Louise J
LJ
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3050, Australia.
Wilson
Nicholas S
NS
Schnorrer
Petra
P
Mount
Adele
A
Lundie
Rachel J
RJ
La Gruta
Nicole L
NL
Crabb
Brendan S
BS
Belz
Gabrielle T
GT
Heath
William R
WR
Villadangos
Jose A
JA
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D051379:Mice; D009113:Muramidase / Q000276:immunology; D010047:Ovalbumin / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology*
D000956:Antigens, Viral; D000949:Histocompatibility Antigens Class II; D014765:Viral Vaccines; D010047:Ovalbumin; D009113:Muramidase