Prevention of peripheral tolerance by a dendritic cell growth factor: Flt3ligand as an adjuvant

Injections of soluble proteins ape poorly immunogenic, and often elicit ant igen-specific tolerance. The mechanism of this phenomenon has been an endur ing 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 1 beta in vivo ape beli eved to recruit and activate professional antigen-presenting cells to the s ite(s) of infection, thereby eliciting immunity. Here we show that administ ration of Flt3 ligand (FL), a cytokine capable of inducing large numbers of dendritic cells (DCs) ill vivo, (a) dramatically enhances the sensitivity oi antigen-specific B and T cell responses to systemic injection of a solub le 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 c ontrolled by DCs, and underscore the potential of FL as a vaccine adjuvant for immunotherapy ill infectious disease and other clinical settings.