Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo

At least two types of interleukin (IL)-15 mRNA isoforms are generated by al ternative splicing at the 5' upstream of exon 5 in mice. To elucidate the p otential roles of IL-15 isoforms in immune responses in vivo, we constructe d two groups of transgenic mice using originally described IL-15 cDNA with a normal exon 5 (normal IL-15 transgenic [Tg] mice) and IL-15 cDNA with an alternative exon 5 (alternative IL-15 Tg mice) under the control of an MHC class I promoter. Normal IL-15 Tg mice constitutionally produced a signific ant level of IL-15 protein and had markedly increased numbers of memory typ e (CD44(high) Ly6C(+)) of CD8(+) T cells in the LN. These mice showed resis tance to Salmonella infection accompanied by the enhanced interferon (IFN)- gamma production, but depletion of CD8(+) T cells exaggerated the bacterial growth, suggesting that the IL-15-dependent CD8(+) T cells with a memory p henotype may serve to protect against Salmonella infection in normal IL-15 Tg mice. On the other hand, a large amount of intracellular IL-15 protein w as detected but hardly secreted extracellularly in alternative IL-15 Tg mic e. Although most of the T cells developed normally ill the alternative IL-1 5 Tg mice, they showed impaired IFN-gamma production upon TCR engagement. T he alternative IL-15 transgenic mice were susceptible to Salmonella accompa nied by impaired production of endogenous IL-15 and IFN-gamma. Thus, two gr oups of IL-15 Tg mice may provide information concerning the different role s of IL-15 isoforms in the immune system in vivo.