Prevention of peripheral tolerance by a dendritic cell growth factor: flt3 ligand as an adjuvant.
Injections of soluble proteins are poorly immunogenic, and often elicit antigen-specific tolerance. The mechanism of this phenomenon has been an enduring puzzle, but it has been speculated that tolerance induction may be due to antigen presentation by poorly stimulatory, resting B cells, which lack specific immunoglobulin receptors for the protein. In contrast, adjuvants, or infectious agents, which cause the release of proinflammatory cytokines such as tumor necrosis factor alpha and interleukin 1beta in vivo are believed to recruit and activate professional antigen-presenting cells to the site(s) of infection, thereby eliciting immunity. Here we show that administration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) in vivo, (a) dramatically enhances the sensitivity of antigen-specific B and T cell responses to systemic injection of a soluble protein, through a CD40-CD40 ligand-dependent mechanism; (b) influences the class of antibody produced; and (c) enables productive immune responses to otherwise tolerogenic protocols. These data support the hypothesis that the delicate balance between immunity and tolerance in vivo is pivotally controlled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy in infectious disease and other clinical settings.
Pulendran
B
B
Immunex Corporation, Seattle, Washington 98101, USA.
Smith
J L
JL
Jenkins
M
M
Schoenborn
M
M
Maraskovsky
E
E
Maliszewski
C R
CR
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D017951:Antigen Presentation; D019013:CD40 Antigens / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D007108:Immune Tolerance; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D008565:Membrane Proteins; C084881:flt3 ligand protein