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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Lack of IL-15 results in the suboptimal priming of CD4(+) T cell response against an intracellular parasite
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Lack of IL-15 results in the suboptimal priming of CD4(+) T cell response against an intracellular parasite

机译：IL-15的缺乏导致针对细胞内寄生虫的CD4（+）T细胞反应的次佳启动

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摘要

IFN-gamma-producing CD4(+) T cells, although important for protection against acute Toxoplasma gondii infection, can cause gut pathology, which may prove to be detrimental for host survival. Here we show that mice lacking IL-15 gene develop a down-regulated IFN-gamma-producing CD4+ T cell response against the parasite, which leads to a reduction in gut necrosis and increased level of survival against infection. Moreover, transfer of immune CD4(+) T cells from WT to IL-15(-/-) mice reversed inhibition of gut pathology and caused mortality equivalent to levels of parental WT mice. Down-regulated CD4+ T cell response in the absence of IL-15, manifested as reduced antigen-specific proliferation, was due to defective priming of the T cell subset by dendritic cells (DCs) of these animals. When stimulated with antigen-pulsed DCs from WT mice, CD4(+) T cells from IL-15(-/-) mice were primed optimally, and robust proliferation of these cells was observed. A defect in the DCs of knockout mice was further confirmed by their reduced ability to produce IL-12 upon stimulation with Toxoplasma lysate antigen. Addition of exogenous IL-15 to DC cultures from knockout mice led to increased IL-12 production by these cells and restored their ability to prime an optimal parasite-specific CD4(+) T cell response. To our knowledge, this is the first demonstration of the role of IL-15 in the development of CD4(+) T cell immunity against an intracellular pathogen. Furthermore, based on these observations, targeting of IL-15 should have a beneficial effect on individuals suffering from CD4(+) T cell-mediated autoimmune diseases.
机译：产生γ-干扰素的CD4（+）T细胞，尽管对预防急性弓形虫感染很重要，但可引起肠道病理，可能对宿主生存有害。在这里，我们显示了缺乏IL-15基因的小鼠对寄生虫产生了下调的IFN-γ产生CD4 + T细胞反应，从而导致肠道坏死的减少和抵抗感染的存活率提高。此外，将免疫CD4（+）T细胞从WT转移至IL-15（-/-）小鼠可逆转肠道病理学的抑制作用，并导致死亡率与亲代WT小鼠相当。在没有IL-15的情况下CD4 + T细胞应答下调，表现为抗原特异性增殖降低，这是由于这些动物的树突状细胞（DC）对T细胞亚群的启动有缺陷。当用来自WT小鼠的抗原脉冲DC刺激时，来自IL-15（-/-）小鼠的CD4（+）T细胞被最佳地引发，并观察到这些细胞的强劲增殖。通过用弓形虫溶胞产物抗原刺激，它们产生IL-12的能力降低，进一步证实了敲除小鼠DC的缺陷。将外源IL-15添加到基因敲除小鼠的DC培养物中，导致这些细胞增加IL-12的产生，并恢复了它们引发最佳寄生虫特异性CD4（+）T细胞应答的能力。据我们所知，这是IL-15在针对细胞内病原体的CD4（+）T细胞免疫发展中的作用的首次证明。此外，基于这些观察结果，靶向IL-15对患有CD4（+）T细胞介导的自身免疫性疾病的个体应具有有益的作用。

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