Interferons α and β as Immune Regulators—A New Look

The type 1 interferons, alpha and beta (IFN- alpha / beta ), are comprised of the products of multiple (up to 12) IFN- alpha genes and a single IFN- beta gene. These factors use a common heterodimeric receptor, broadly expressed on most cells. The major pathway of intracellular signaling used by IFN- alpha / beta and their receptors accesses the tyrosine kinases, Jak 1 and Tyk 2, activating the signal transducer and activators of transcription (STAT) 1 and STAT2 to form a STAT1/STAT2 heterodimer. Other pathways, however, are also induced. STAT1/STAT2 complexes associate with a p48 protein, identified as the interferon responsive factor (IRF) 9, to form the interferon-stimulated gene factor-3 (ISGF-3). ISGF-3 induces transcription as a result of recognizing interferon stimulated response elements (ISREs) in promoter regions of interferon responsive genes. Although first characterized based on potent antiviral functions, IFN- alpha / beta also mediate a variety of immunoregulatory effects. The immune modulating functions suggest that type 1 IFNs may be important links between innate and adaptive immune responses. IFN- alpha / beta induction of MHC class I expression and activation of natural killer (NK) cell cytotoxicity has long been appreciated. The last few years of research have not only advanced the characterization of these classic IFN activities but have also revealed a number of surprises concerning other biologically important immunoregulatory functions. The strongest evidence is for IFN- alpha / beta enhancement of induction of other IFN- alpha / beta cytokines and IL-15; the apparently contrasting inhibition of IL-12 expression but induction of a high-affinity form of the IL-12 receptor; the shaping of NK cell responses; the complex positive and negative effects on IFN- gamma expression; and effects on dendritic cell (DC) maturation and function. These are reviewed below.