Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite
Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite
复制标题
DOI：
10.1073/pnas.0506180103
复制
发表时间：
2006-04-25
影响因子：
11.1
通讯作者：
Khan, IA
中科院分区：
文献类型：
--
作者：
Combe, CL;Moretto, MM;Khan, IA
产生 IFN-γ 的 CD4(+) T 细胞虽然对于预防急性弓形虫感染很重要，但也可能引起肠道病理，这可能不利于宿主的生存。在这里，我们发现缺乏 IL-15 基因的小鼠会产生下调的产生 IFN-γ 的 CD4+ T 细胞对抗寄生虫的反应，从而减少肠道坏死并提高抗感染的存活率。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的抑制，并导致与亲代WT小鼠水平相当的死亡率。在没有 IL-15 的情况下，CD4+ T 细胞反应下调，表现为抗原特异性增殖减少，这是由于这些动物的树突状细胞 (DC) 对 T 细胞亚群的启动缺陷所致。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细胞得到最佳激发，并且观察到这些细胞的强劲增殖。敲除小鼠 DC 的缺陷进一步得到证实，即在弓形虫裂解物抗原刺激下，它们产生 IL-12 的能力降低。在敲除小鼠的 DC 培养物中添加外源性 IL-15 可以增加这些细胞产生的 IL-12，并恢复其引发最佳寄生虫特异性 CD4(+) T 细胞反应的能力。据我们所知，这是首次证明 IL-15 在针对细胞内病原体的 CD4(+) T 细胞免疫发展中的作用。此外，基于这些观察，靶向IL-15应该对患有CD4(+)T细胞介导的自身免疫性疾病的个体产生有益的影响。
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.