Dendritic cells (DCs) are essential for the initiation of immune responses by capturing, processing and presenting antigens to T cells. Antigen capture stimulates the maturation of DCs and their subsequent migration to lymphoid organs where they present antigens to T cells. Converting from an antigen-capturing to an antigen-presenting mode is defined as DC maturation (for reviews, see references 1-4). DC maturation is a key checkpoint in the initiation of immunity and is important for the overall quality of an immune response.5
Production of cytokines such as IL-10 and IL-12 during their maturation process can influence DC induction of a Th1 or Th2 immune response. In addition to expressing high levels of antigen-presenting molecules and costimulatory molecules, mature DCs release large amounts of IL-12, which can stimulate a Th1 immune response. Release of IL-10, however, blocks the DC maturation process by interfering with up-regulation of costimulatory molecules and production of IL-12, subsequently limiting the ability of DCs to initiate a Th1 response.5,6 Two recently published studies evaluate the influence of autocrine production of IL-10 and IL-12 on DC maturation and induction of immune responses.5,7
Autocrine IL-10 prevents spontaneous maturation of DCs in vitro and increases IL-10 production by DCs.5 Immature monocyte-derived DCs release low levels of IL-10. Expression of IL-10 increases after DC stimulation. Exposing DCs to anti-IL-10 neutralizing antibodies reduces IL-10 expression and enhances release of TNF-alpha and IL-12. It also activates the transition of naïve T cells to Th1 cells. Endogenous IL-10, however, limits the ability of autocrine IL-10 to suppress DC maturation and also limits the antigen-presenting functions of DCs, thus reducing the ability of DCs to initiate Th1 responses. Mature DCs lose sensitivity to IL-10, but the reason for this is unknown.
When present during DC maturation, IL-10 suppresses IL-12 production, thus inhibiting IFN-gamma up-regulation.5-7 Autocrine IL-12 is necessary for IFN-gamma production by DCs.7 Expression of STAT4, a signal transduction molecule important in cytokine-induced gene expression, appears central to IL-12 induced DC production of IFN-gamma.7 Mature DCs express high levels of Stat 4, whereas immature DCs express low levels of STAT4.7 STAT4 levels directly correlate with IFN-gamma production by DCs.7 STAT4(-/-) DCs do not produce IFN-gamma, thus supporting a role for STAT4 in IL-12-dependent IFN-gamma production.7 It is unknown, however, whether or not STAT4 affects the IFN-gamma gene.7