Type I interferon inhibits phosphorylation of AKT to impair T cell proliferation induced by interleukin-7 (P6315)

Abstract

Abstract Type I interferons (IFN-I) have anti-proliferative activity and are elevated in chronic HIV infection. We hypothesized IFN-I may adversely affect T cell homeostasis by limiting T cell proliferation in response to interleukin-7 (IL-7). Peripheral blood mononuclear cells (PBMC) or purified CD4+ T cells were CFSE-labeled and incubated with IL-7 (5ng/ml) plus or minus interferon alpha (30-500 U/ml) in X-vivo serum-free medium. T cell proliferation was assessed by CFSE dye dilution at 7 d. T cell function was examined by stimulating cells with SEB and measuring IFN-g, IL-2 and CD40L expression by intracellular flow cytometry. Intracellular expression of P-STAT5 and pAKT were measured at 1-3 d. CD4+ T cells incubated with IL-7 proliferated less efficiently in the presence of IFN-I (n=10; p<0.05). Moreover, these cells were less functional as indicated by reduced IL-2, CD40L and IFN-g production, with the greatest impairments observed for IL-2 production. Inhibition of either pAKT or P-STAT5 with chemical inhibitors also blocked T cell proliferation indicating that these pathways are both important in IL-7-induced proliferation of T cells. Analyses of IL-7-induced signaling pathways indicated that IFN-I impaired pAKT signaling (p<0.05) but had limited effect on P-STAT5 signaling. These results suggest that IFN-I has the potential to interfere with T cell homeostatic proliferation by inhibiting pAKT activation.