Caamaño J, Tato C, Cai G, Villegas E N, Speirs K, Craig L, Alexander J, Hunter C A
Medical Research Council Centre for Immune Regulation, School of Medicine, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
J Immunol. 2000 Nov 15;165(10):5720-8. doi: 10.4049/jimmunol.165.10.5720.
The NF-kappaB family of transcription factors are involved in the regulation of innate and adaptive immune functions associated with resistance to infection. To assess the role of NF-kappaB(2) in the regulation of cell-mediated immunity, mice deficient in the NF-kappaB(2) gene (NF-kappaB(2)(-/-)) were challenged with the intracellular parasite Toxoplasma gondii. Resistance to this opportunistic pathogen is dependent on the production of IL-12, which is required for the development of innate NK cell and adaptive T cell responses dominated by the production of IFN-gamma necessary to control replication of this parasite. Although wild-type controls were resistant to T. gondii, NF-kappaB(2)(-/-) mice developed severe toxoplasmic encephalitis and succumbed to disease between 3 and 10 wk following infection. However, NF-kappaB(2) was not required for the ability of macrophages to produce IL-12 or to inhibit parasite replication and during the acute stage of infection, NF-kappaB(2)(-/-) mice had no defect in their ability to produce IL-12 or IFN-gamma and infection-induced NK cell responses appeared normal. In contrast, during the chronic phase of the infection, susceptibility of NF-kappaB(2)(-/-) mice to toxoplasmic encephalitis was associated with a reduced capacity of their splenocytes to produce IFN-gamma associated with a loss of CD4(+) and CD8(+) T cells. This loss of T cells correlated with increased levels of apoptosis and with elevated expression of the pro-apoptotic molecule Fas by T cells from infected NF-kappaB(2)(-/-) mice. Together, these results suggest a role for NF-kappaB(2) in the regulation of lymphocyte apoptosis and a unique role for this transcription factor in maintenance of T cell responses required for long-term resistance to T. gondii.
转录因子NF-κB家族参与调控与抗感染抵抗力相关的固有免疫和适应性免疫功能。为了评估NF-κB(2)在细胞介导的免疫调节中的作用，用细胞内寄生虫刚地弓形虫攻击NF-κB(2)基因缺陷小鼠（NF-κB(2)(-/-)）。对这种机会性病原体的抵抗力取决于IL-12的产生，而IL-12是固有NK细胞发育以及由控制该寄生虫复制所必需的IFN-γ产生主导的适应性T细胞反应所必需的。尽管野生型对照对刚地弓形虫有抵抗力，但NF-κB(2)(-/-)小鼠发生了严重的弓形虫脑炎，并在感染后3至10周内死于该病。然而，巨噬细胞产生IL-12或抑制寄生虫复制的能力并不需要NF-κB(2)，并且在感染急性期，NF-κB(2)(-/-)小鼠产生IL-12或IFN-γ的能力没有缺陷，感染诱导的NK细胞反应看起来正常。相反，在感染的慢性期，NF-κB(2)(-/-)小鼠对弓形虫脑炎的易感性与其脾细胞产生IFN-γ的能力降低有关，这与CD4(+)和CD8(+) T细胞的丧失有关。T细胞的这种丧失与凋亡水平升高以及感染的NF-κB(2)(-/-)小鼠的T细胞促凋亡分子Fas表达升高相关。总之，这些结果表明NF-κB(2)在淋巴细胞凋亡调节中起作用，并且该转录因子在维持对刚地弓形虫长期抵抗力所需的T细胞反应中具有独特作用。
