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Interferon- Inhibits Proliferation in Human T Lymphocytes by Abrogation of Interleukin 2-induced Changes in Cell Cycle-regulatory Proteins¹

Department of Oncology and Pathology, Radiumhemmet, Karolinska Hospital and Institute, S-171 76 Stockholm, Sweden

IFN- exerts prominent regulatory functions on the immune system. One such effect is the inhibition of proliferation of in vitro stimulated T lymphocytes. The exact physiological function of this activity is not known, but it has been implicated in the antiviral effects of IFN, its antitumor action in T-cell malignancies, and the regulation of the in vivo T-cell response. Here, we have investigated the mechanism underlying the IFN--mediated growth inhibition of normal human PHA- and IL-2-stimulated T lymphocytes by an analysis of how IFN- treatment influences known molecular events that normally accompany the transition from quiescence to proliferation in these cells.

IFN- treatment was found to profoundly block S-phase entry of stimulated T lymphocytes. This correlated with a strong inhibition of IL-2-induced changes in G₁-regulatory proteins, including the prevented up-regulation of G₁ cyclins and cyclin-dependent kinases as well as an abrogation of mitogen-induced reduction of p27^Kip1 levels. This latter effect was due to a maintained stability of the p27^Kip1 protein in the IFN--treated cells. In line with these findings, phosphorylation of the pocket proteins was abrogated in IFN--treated cells. Furthermore, our data indicate that IFN- has selective effects on the pathways that emerge from the IL-2 receptor because IFN- treatment does not block IL-2-induced up-regulation of c-myc or Cdc25A.

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