Type I interferons produced by dendritic cells promote their phenotypic and functional activation

Abstract

Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infectioninduced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-␣ and IFN-␤, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. IntroductionDendritic cells (DCs) are recognized as the key antigen-presenting cells (APCs) controlling the initiation of T cell-dependent immune responses. 1 DCs not only are the most potent APCs for activation of resting T cells, but can also regulate the type of response made, dictating the cytokines expressed by responding T cells. 2 Furthermore, DCs have the ability to down-regulate T-cell activation and may play a role in the induction of tolerance. [3][4][5] The type of response elicited by particular DCs is likely to reflect their developmental origin, anatomical location, and state of activation. 6 Immature (resting) DCs reside in most tissues and are efficient in binding and internalizing antigens. 1 However, these cells are relatively poor at presenting antigen and inducing T-cell activation, owing at least in part to their low cell surface expression of costimulatory and adhesion molecules. In response to a variety of stimuli (see below), DCs undergo a process that has been variably termed activation or maturation, during which they lose their capacity for antigen uptake and acquire potent T-cell stimulatory ability. This is associated with up-regulation of cell surface major histocompatibility complex (MHC) class II, costimulatory molecules (eg, CD80, CD86, CD40), and adhesion molecules (eg, CD54). 1 DC activation can be induced by signals that have been described as indicative of "danger," such as heat shock proteins, 7 mechanical manipulation, 8 or exposure to necrotic cells, 8,9 as well as components of the extracellular matrix, 10 interaction with activated (CD40 ligand-expressing)T cells, 11-14 and infection. DCs are particularly tuned to recognition of infection, as DC activation can be stimulated by exposure to whole pathogens (viruses or bacteria [15][16][17] One family of infection-induced cytokines that can activate DCs is the type I interferons (type I IFNs). Type I IFNs include a number of evolutionarily conserv...

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Immunisation with ‘naïve’ syngeneic dendritic cells protects mice from tumour challenge

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