An alternatively spliced IL-15 isoform modulates cell activation via inducing differential IL-15 receptor-dependent signaling pathways (CCR3P.203)

Abstract

Abstract IL-15 is a pleiotropic cytokine mediating proliferation and survival of memory CD8+ T cells, natural killer (NK) and NKT cells as well as enhancing cytokine production. Deregulated and excessive expression of IL-15 has been implicated in promoting pathophysiologic state for human inflammatory diseases and malignant transformation. In a routine phenotype-driven screen, we identified a point mutation in exon 7 of the IL-15 gene in Pedigree 191 of N-ethyl-N-nitrosourea (ENU) mutagenized mice which expressed a depressed level of CD44 in CD8+ T cells (called DM for deficiency in memory) and resulted in an increased expression of alternatively spliced IL-15 isoform (IL-15ΔE7). Mechanical stimulation of DM skin reduced keratinocyte activation. Ectopic expression of IL-15ΔE7 in WT skin profoundly blocked neutrophil infiltration to inflamed skin induced by abrasion, sodium dodecyl sulfate or immiquimod treatment, suggesting a regulatory role of IL-15∆E7 in mediating proinflammatory response in skin. While treating T cells with recombinant soluble IL-15∆E7 protein activated a transient but delayed activation of MAPK/p38, IL-15∆E7 failed to activate phosphorylation of STAT5 and its downstream target bcl-2 expression. The capacity of IL-15ΔE7 in inducing differential signaling has pointed IL-15ΔE7 as a potential therapeutic agent for treating inflammatory disorders.