Type I Interferon Signaling Pathway May Be Involved in Optimal Interleukin-2 Production in CD4+ T Cells

Previous studies demonstrate that interferon alpha (IFN-α) promotes human T helper 1 memory development by positively regulating interleukin-2 (IL-2) expression, a hallmark cytokine of central memory CD4⁺ T cells. The present work seeks to delineate how signaling through the interferon alpha/beta receptor promotes IL-2 secretion in murine CD4⁺ T cell. IL-2 provides an essential growth signal to naïve and memory T cells. Examining naïve OT-II interferon alpha-receptor-2 (IFNAR2) knockout CD4⁺ T cells in vitro, we observed conflicting results in secreted IL-2 protein at 72 hours post-stimulation and intracellular IL-2 protein expression at 48 hours post-stimulation. Subsequent studies suggest this was not due to lack of proliferation or an inherit defect in IL-2 secretion. In response to an in vivo vesicular stomatitis virus infection, OT-II IFNAR2 knockout CD4⁺ T cells displayed defective expansion at seven days post-infection. Signaling through the interferon alpha-receptor may enhance IL-2 expression in CD4⁺ T cells, indicating a possible role for downstream transcription factors in sustaining IL-2 expression. Interestingly, CD4⁺ T cells with a carboxy-terminal substitution in the signal transducer of activator of transcription-2 (STAT2) protein may display a similar defect in T cell receptor mediated IL-2 expression. IFNAR2 knockout and STAT2 knock-in splenocytes may display a defect in IL-2 mRNA expression as early as twelve hours post-stimulation. However, IL-2 promoter activity in OT-II IFNAR2 knockout CD4⁺ T cells is insignificantly increased compared to OT-II wild-type cells, suggesting analysis of IL-2 mRNA stability be examined more closely. Preliminary data suggests STAT2 may translocate to the nucleus in response to TCR stimulation in CD4⁺ T cells and could potentially bind to a putative interferon stimulated response element within the IL-2 promoter. Our findings provide insight into how the type I IFN signaling pathway may play a role regulate IL-2 expression in CD4⁺ T cells.