Dynamics of IL-15/IL-15R-alpha expression in response to HSV-1 infection reveal a novel mode of viral immune evasion counteracted by iNKT cells

Herpes simplex virus type 1 (HSV-1) infects and persists in most of the human population. Interleukin-15 (IL-15) has an important role in the activation of cell-mediated immune responses and acts in complex with IL-15 receptor alpha (IL-15R-alpha) through cell surface transpresentation. Here, we have examined the IL-15/IL-15R-alpha complex response dynamics during HSV-1 infection in human keratinocytes. Surface expression of the IL-15/IL-15R-alpha complex rapidly increased in response to HSV-1, reaching a peak around 12 h after infection. This response was dependent on detection of viral replication by TLR3, and enhancement of IL15 and IL15RA gene expression. Beyond the peak of expression, levels of IL-15 and IL-15R-alpha gradually declined, reaching a profound loss of surface expression beyond 24 h of infection. This involved the loss of IL15 and IL15RA transcription. Interestingly, invariant natural killer T (iNKT) cells inhibited the viral interference with IL-15/IL-15R-alpha complex expression in an IFN gamma-dependent manner. These results indicate that rapid upregulation of the IL-15/IL-15R-alpha complex occurs in HSV-1 infected keratinocytes, and that this response is targeted by viral interference. Shutdown of the IL-15 axis represents a novel mode of HSV-1 immune evasion, which can be inhibited by the host iNKT cell response.