IFN-alpha 2b reduces IL-2 production and IL-2 receptor function in primaryCD4(+) T cells

Initially described as an antiviral cytokine, IFN-alpha has been subsequent ly shown to affect several cellular functions, including cellular different iation and proliferation. For these reasons, IFN-alpha is currently used in clinical practice for the treatment of viral infections and malignancies. In this manuscript, we show two novel mechanisms concomitantly responsible for the antiproliferative effect of IFN-alpha. First, long-term treatment w ith IFN-alpha of primary CD4(+) T cells reduced surface expression of CD3 a nd CD28 These events resulted in decreased phosphorylation of the mitogen-a ctivated extracellular signal-regulated activating kinase and its substrate extracellular signal-regulated kinase, leading to diminished production of IL-2. Second, IFN-alpha treatment of primary CD4(+) T cells reduced prolif erative response to stimulation in the presence of exogenous IL-2 by marked ly decreasing mRNA synthesis and surface expression of CD25 (alpha-chain), a critical component of the IL-2R complex. These results may be relevant fo r the antitumor effects of IFN-alpha and may help us to better understand i ts detrimental role in the inhibition of proliferation of the bulk of CD4() T cells (uninfected cells) in HIV-infected persons, who are known to over produce IFN-alpha.