Interferon-α inhibits CD4 T cell responses to interleukin-7 and interleukin-2 and selectively interferes with Akt signaling

Persistent type I IFN production occurs during chronic viral infections, such as HIV disease. As type I IFNs have antiproliferative activity, it is possible that chronic exposure to these cytokines could adversely affect T cell homeostasis. We investigated the capacity of IFN-alpha to impair T cell proliferation induced by the homeostatic cytokine, IL-7, or another common g-chain cytokine, IL-2, in cells from healthy human donors. We found that IL-7-or IL-2-induced proliferation of CD4(+) T cells was partially inhibited in the presence of IFN-alpha. The CD4(+) T cells that were exposed to IFN-alpha also displayed attenuated induction of IL-2 and CD40L following TCR stimulation. Analyses of signaling pathways indicated that IL-7 and IL-2 induced a delayed and sustained P-Akt signal that lasted for several days and was partially inhibited by IFN-alpha. In contrast, IL-7-induced P-STAT5 was not affected by IFN-alpha. Furthermore, IFN-alpha had no detectable effect on P-Akt that was induced by the chemokine SDF-1. Both inhibitors of P-Akt and P-STAT5 blocked IL-7-induced T cell proliferation, confirming that both signaling pathways are important for IL-7-induced T cell proliferation. These results demonstrate that IFN-alpha can selectively inhibit cytokine-induced P-Akt as a potential mechanism to disrupt homeostasis of T lymphocytes.