IFN-α2b reduces IL-2 production and IL-2 receptor function in primary CD4⁺ T cells

Initially described as an antiviral cytokine, IFN-α has been subsequently shown to affect several cellular functions, including cellular differentiation and proliferation. For these reasons, IFN-α 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-α. First, long-term treatment with IFN-α of primary CD4⁺ T cells reduced surface expression of CD3 and CD28. These events resulted in decreased phosphorylation of the mitogen-activated extracellular signal-regulated activating kinase arid its substrate extracellular signal-regulated kinase, leading to diminished production of IL-2. Second, IFN-α treatment of primary CD4⁺ T cells reduced proliferative response to stimulation in the presence of exogenous IL-2 by markedly decreasing mRNA synthesis and surface expression of CD25 (α-chain), a critical component of the IL-2R complex. These results may be relevant for the antitumor effects of IFN-α and may help us to better understand its detrimental role in the inhibition of proliferation of the bulk of CD4⁺ T cells (uninfected cells) in HIV-infected persons, who are known to overproduce IFN-α.