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Differential roles of interleukin 15 mRNA isoforms generated by alternative splicing in immune responses in vivo
H Nishimura1, T Yajima, Y Naiki
1Laboratory of Host Defense & Germfree Life, Research Institute for Disease Mechanism and Control, Nagoya University School of Medicine, Nagoya 466, Japan. nishihit@med.nagoya-u.ac.jp
Abstract:
At least two types of interleukin (IL)-15 mRNA isoforms are generated by alternative splicing at the 5' upstream of exon 5 in mice. To elucidate the potential roles of IL-15 isoforms in immune responses in vivo, we constructed 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 significant level of IL-15 protein and had markedly increased numbers of memory type (CD44(high) Ly6C(+)) of CD8(+) T cells in the LN. These mice showed resistance 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 phenotype 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 was detected but hardly secreted extracellularly in alternative IL-15 Tg mice. Although most of the T cells developed normally in the alternative IL-15 Tg mice, they showed impaired IFN-gamma production upon TCR engagement. The alternative IL-15 transgenic mice were susceptible to Salmonella accompanied by impaired production of endogenous IL-15 and IFN-gamma. Thus, two groups of IL-15 Tg mice may provide information concerning the different roles of IL-15 isoforms in the immune system in vivo.
Insights
Two interleukin-15 (IL-15) mRNA isoforms in mice impact immune responses. Normal IL-15 transgenic mice showed enhanced CD8(+) T cell memory and Salmonella resistance, while alternative IL-15 transgenic mice exhibited impaired immunity.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Interleukin-15 (IL-15) is crucial for immune cell development and function.
- Alternative splicing of IL-15 mRNA generates distinct isoforms with potentially different biological activities.
- Understanding IL-15 isoform function is key to deciphering complex immune responses.
Purpose of the Study:
- To investigate the in vivo roles of two IL-15 mRNA isoforms generated by alternative splicing.
- To compare the immune responses and disease resistance in transgenic mice expressing normal versus alternative IL-15 isoforms.
Main Methods:
- Construction of two transgenic mouse lines: normal IL-15 cDNA and alternative IL-15 cDNA.
- Expression analysis of IL-15 protein and immune cell populations (CD8(+) T cells).
- Assessment of resistance to Salmonella infection and interferon-gamma (IFN-gamma) production.
Main Results:
- Normal IL-15 transgenic mice exhibited increased memory CD8(+) T cells, enhanced IFN-gamma production, and resistance to Salmonella infection.
- Depletion of CD8(+) T cells in normal IL-15 transgenic mice exacerbated bacterial growth.
- Alternative IL-15 transgenic mice showed impaired extracellular IL-15 secretion, reduced IFN-gamma production, and susceptibility to Salmonella.
Conclusions:
- IL-15 isoforms play distinct roles in regulating CD8(+) T cell memory and immune defense against bacterial infections.
- The normal IL-15 isoform promotes protective immunity, likely via memory CD8(+) T cells.
- The alternative IL-15 isoform may impair immune responses due to altered IL-15 secretion and function.