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2b Reduces IL-2 Production and IL-2 Receptor Function in Primary CD4+ T Cells
*
Institute of Human Virology, University of Maryland Biotechnology Institute and University of Maryland Medical Center, Baltimore, MD 21201;
Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy;
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
§
Institute Pierre and Marie Curie, Paris, France
Initially described as an antiviral cytokine, IFN-
has been
subsequently shown to affect several cellular functions, including
cellular differentiation and proliferation. For these reasons, IFN-
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-. First, long-term treatment with IFN- 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- 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 (-chain), a critical component of the
IL-2R complex. These results may be relevant for the antitumor effects
of IFN- 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-.
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