Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC., USA.
PLoS One. 2010 May 26;5(5):e10842. doi: 10.1371/journal.pone.0010842.
CD8(+) T cells play an essential role in the protection against both acute as well as chronic Toxoplasma gondii infection. Although the role of IL-15 has been reported to be important for the development of long-term CD8(+) T cell immunity against the pathogen, the simultaneous roles played by both IL-15 and related gamma-chain family cytokine IL-7 in the generation of this response during acute phase of infection has not been described. We demonstrate that while lack of IL-7 or IL-15 alone has minimal impact on splenic CD8(+) T cell maturation or effector function development during acute Toxoplasmosis, absence of both IL-7 and IL-15 only in the context of infection severely down-regulates the development of a potent CD8(+) T cell response. This impairment is characterized by reduction in CD44 expression, IFN-gamma production, proliferation and cytotoxicity. However, attenuated maturation and decreased effector functions in these mice are essentially downstream consequences of reduced number of antigen-specific CD8(+) T cells. Interestingly, the absence of both cytokines did not impair initial CD8(+) T cell generation but affected their survival and differentiation into memory phenotype IL-7Ralpha(hi) cells. Significantly lack of both cytokines severely affected expression of Bcl-2, an anti-apoptotic protein, but minimally affected proliferation. The overarching role played by these cytokines in eliciting a potent CD8(+) T cell immunity against T. gondii infection is further evidenced by poor survival and high parasite burden in anti IL-7 treated IL-15(-/-) mice. These studies demonstrate that the two cytokines, IL-7 and IL-15, are exclusively important for the development of protective CD8(+) T cell immune response against T. gondii. To the best of our knowledge this synergism between IL-7 and IL-15 in generating an optimal CD8(+) T cell immunity against intracellular parasite or any other infectious disease model has not been previously reported.
CD8(+) T 细胞在抵抗急性和慢性弓形虫感染中起着至关重要的作用。虽然已经报道了白细胞介素 15 (IL-15) 对病原体的长期 CD8(+) T 细胞免疫的发展具有重要作用，但在感染的急性期，IL-15 和相关的γ链家族细胞因子白细胞介素 7 (IL-7) 同时在产生这种反应中的作用尚未被描述。我们证明，虽然单独缺乏 IL-7 或 IL-15 对急性弓形虫病期间脾脏 CD8(+) T 细胞的成熟或效应功能的发展影响最小，但仅在感染的情况下同时缺乏 IL-7 和 IL-15 会严重下调强有力的 CD8(+) T 细胞反应的发展。这种损伤的特征是 CD44 表达、IFN-γ产生、增殖和细胞毒性降低。然而，在这些小鼠中，成熟度降低和效应功能降低基本上是抗原特异性 CD8(+) T 细胞数量减少的下游后果。有趣的是，缺乏这两种细胞因子不会损害初始 CD8(+) T 细胞的产生，但会影响它们的存活和分化为记忆表型 IL-7Ralpha(hi)细胞。值得注意的是，缺乏这两种细胞因子都不会影响 Bcl-2 的表达，Bcl-2 是一种抗凋亡蛋白，但对增殖的影响最小。这些细胞因子在引发针对弓形虫感染的强烈 CD8(+) T 细胞免疫中的主导作用进一步通过抗 IL-7 处理的 IL-15(-/-) 小鼠的存活率低和寄生虫负荷高得到证实。这些研究表明，这两种细胞因子，白细胞介素 7 和白细胞介素 15，对于针对弓形虫的保护性 CD8(+) T 细胞免疫反应的发展是至关重要的。据我们所知，IL-7 和 IL-15 之间的这种协同作用在产生针对细胞内寄生虫或任何其他传染病模型的最佳 CD8(+) T 细胞免疫方面尚未被报道。
