Gill Navkiran, Ashkar Ali A
Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics, McMaster University Health Sciences Centre, Hamilton, Ontario, Canada.
J Virol. 2009 Jan;83(2):918-26. doi: 10.1128/JVI.01282-08. Epub 2008 Nov 12.
Interleukin-15 (IL-15) is necessary for the development and function of NK/NKT cells and the maintenance of naive and memory CD8(+) T cells. In the absence of IL-15, protective innate immunity is not available; however, a functional adaptive immune response against vaginal herpes simplex virus 2 (HSV-2) is generated. Mice overexpressing IL-15 (IL-15tg mice) have higher numbers of NK cells, greater NK-derived gamma interferon, and more CD8(+) T cells. Here we examined the consequences of IL-15 overexpression for innate and adaptive immunity against genital HSV-2. Surprisingly, IL-15tg mice immunized against HSV-2 were not protected against genital HSV-2 challenge compared to control immunized mice. IL-15tg mice had a higher frequency of NK cells in the genital mucosa than control mice. However, immunized IL-15tg mice had significantly lower numbers of HSV-2-specific CD4(+) T cells than B6 mice. We then confirmed that CD4(+) T cells, but not CD8(+) T cells, are essential for protection against intravaginal HSV-2 challenge. Since we observed less protection in immunized IL-15tg mice, we then examined if the adaptive immune responses generated in an environment with overexpression of IL-15 could provide protection against HSV-2 in an environment with normal levels of IL-15 expression. We adoptively transferred immunized cells from IL-15tg and B6 mice into naive RAG-1(-/-) mice and found that the cells from immunized IL-15tg mice were able to provide protection in this IL-15-normal environment. Our data suggest that overexpression of IL-15 results in a reduced CD4(+) T cell-mediated adaptive immune response against genital HSV-2.
白细胞介素-15（IL-15）对于自然杀伤细胞/自然杀伤T细胞（NK/NKT细胞）的发育和功能以及初始和记忆性CD8(+) T细胞的维持是必需的。在缺乏IL-15的情况下，无法获得保护性固有免疫；然而，针对阴道单纯疱疹病毒2型（HSV-2）会产生功能性适应性免疫反应。过表达IL-15的小鼠（IL-15转基因小鼠）具有更多数量的NK细胞、更多源自NK的γ干扰素以及更多的CD8(+) T细胞。在此，我们研究了IL-15过表达对针对生殖器HSV-2的固有免疫和适应性免疫的影响。令人惊讶的是，与对照免疫小鼠相比，用HSV-2免疫的IL-15转基因小鼠在面对生殖器HSV-2攻击时并未受到保护。IL-15转基因小鼠生殖器黏膜中的NK细胞频率高于对照小鼠。然而，免疫后的IL-15转基因小鼠中HSV-2特异性CD4(+) T细胞的数量明显低于B6小鼠。然后我们证实，对于抵御阴道内HSV-2攻击而言，CD4(+) T细胞而非CD8(+) T细胞至关重要。由于我们在免疫后的IL-15转基因小鼠中观察到保护作用较弱，于是我们研究了在IL-15过表达环境中产生的适应性免疫反应是否能在IL-15表达水平正常的环境中为抵御HSV-2提供保护。我们将来自IL-15转基因小鼠和B6小鼠的免疫细胞过继转移至未免疫的RAG-1(-/-)小鼠体内，发现来自免疫后的IL-15转基因小鼠的细胞能够在这种IL-15正常的环境中提供保护。我们的数据表明，IL-15的过表达会导致针对生殖器HSV-2的CD4(+) T细胞介导的适应性免疫反应减弱。
