Massive interleukin-12-induced interferon-γ production by interleukin-15-stimulated lamina propria lymphocytes followed by down-regulation of the interleukin-12 receptor

Abstract

The intestinal mucosal immune response must differentiate between harmless foreign antigens and pathogens, a distinction that may depend upon changes in the cytokine milieu. A key cytokine in the adaptive immune response is interleukin-12 (IL-12), secreted by antigen-presenting cells (APC) immediately after encounter with a pathogen. IL-12 is important in the priming and polarization of naïve T cells. Here, we show that IL-12 and IL-15 direct human intestinal lamina propria lymphocytes (LPL) in the absence of T-cell receptor engagement to secrete extremely high amounts of interferon-gamma (IFN-gamma), greater than with any other stimulus. The functional synergy of IL-12 with IL-15 surprisingly operates independently of signal transducer and activator of transcription 1 (STAT1), STAT3, STAT4, or STAT5 phosphorylation and occurs during transcription. Four-colour immunofluorescence showed that IL-12 receptor beta1 is found on the CD4+ T cells expressing intracytoplasmic IFN-gamma. Importantly, IL-12 receptors beta1 and beta2 are not up-regulated by IL-12, unlike findings using antigen-specific T cells, and are lost over time. This study demonstrates the early and massive IFN-gamma response of LPL to IL-12 and IL-15, providing the tools to deal with a pathogen. The down-regulation of IL-12 receptors may curtail any excess damaging inflammation.