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IFN-alpha 2b reduces IL-2 production and IL-2 receptor function in primary CD4+ T cells
D Zella1, F Romerio, S Curreli
1Institute of Human Virology, University of Maryland Biotechnology Institute and University of Maryland Medical Center, Baltimore, MD 21201, USA. zella@umbi.umd.edu
Abstract:
Initially described as an antiviral cytokine, IFN-alpha has been subsequently shown to affect several cellular functions, including cellular differentiation 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 with IFN-alpha 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 and its substrate extracellular signal-regulated kinase, leading to diminished production of IL-2. Second, IFN-alpha 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 (alpha-chain), a critical component of the IL-2R complex. These results may be relevant for the antitumor effects of IFN-alpha 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-alpha.
Insights
Interferon-alpha (IFN-alpha) inhibits CD4+ T cell proliferation through two novel mechanisms: reducing CD3/CD28 expression and decreasing CD25 (IL-2 receptor alpha-chain) synthesis, impacting its use in treating viral infections and malignancies.
Area of Science:
- Immunology
- Cell Biology
Background:
- Interferon-alpha (IFN-alpha) is a cytokine with known antiviral and antitumor properties.
- IFN-alpha influences cellular differentiation and proliferation, leading to its clinical use in treating viral infections and cancers.
Purpose of the Study:
- To elucidate two novel mechanisms by which IFN-alpha exerts its antiproliferative effects on CD4+ T cells.
- To understand the implications of these mechanisms for IFN-alpha's therapeutic applications and its role in HIV pathogenesis.
Main Methods:
- Primary CD4+ T cells were treated with IFN-alpha.
- Surface expression of CD3 and CD28, and CD25 (IL-2 receptor alpha-chain) were analyzed.
- Phosphorylation of ERK and IL-2 production were measured.
- mRNA synthesis of CD25 was assessed.
Main Results:
- Long-term IFN-alpha treatment reduced CD3 and CD28 surface expression on CD4+ T cells.
- This reduction led to decreased ERK phosphorylation and diminished IL-2 production.
- IFN-alpha also decreased CD25 mRNA synthesis and surface expression, impairing response to IL-2.
- Overall proliferative capacity of CD4+ T cells was reduced.
Conclusions:
- IFN-alpha inhibits CD4+ T cell proliferation via downregulation of T cell receptor signaling components and IL-2 pathway.
- These findings enhance understanding of IFN-alpha's antitumor effects.
- The study sheds light on IFN-alpha's detrimental role in CD4+ T cell proliferation inhibition in HIV-infected individuals.