Lymphotoxin αβ2 (Membrane lymphotoxin) is critically important for resistance to Leishmania major infection in mice
Lymphotoxin αβ2 (Membrane lymphotoxin) is critically important for resistance to Leishmania major infection in mice
复制标题
DOI：
10.4049/jimmunol.179.8.5358
复制
发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
Uzonna, Jude E.
中科院分区：
文献类型：
--
作者：
Xu, Guilian;Liu, Dong;Uzonna, Jude E.
尽管tnf - α在控制包括利什曼原虫在内的细胞内病原体中的重要作用已得到证实，但相关细胞因子淋巴素α β 2 （LT α 1 β 2，膜淋巴素）是否在这一过程中发挥作用尚不确定。在这项研究中，我们利用耐药C57BL/6背景下的LT β缺陷（LT β(-/-)）小鼠，研究了膜淋巴毒素在宿主对L. major感染反应中的作用。尽管早期免疫反应与野生型（WT）小鼠相当，但LT β(-/-)小鼠由于伴有不受控制的寄生虫增殖的进行性和无法解决的炎症而发展为慢性无法愈合的皮肤病变。这种慢性疾病与感染小鼠脾细胞IL-12和ag特异性ifn - γ产生的显著减少有关。与细胞免疫反应缺陷一致，与WT小鼠相比，感染的LT β(-/-)小鼠血清中ag特异性IgG1和IgG2a水平显著降低。虽然给L. major感染的LT β(-/-)小鼠注射il -12可以完全解决慢性病变，但它只能部分（但显著）减少寄生虫的增殖。相反，在受感染的LT β(-/-)小鼠中，阻断LIGHT信号导致急性和进行性病变发展，大量寄生虫增殖和传播到内脏器官。尽管感染的LT β (-/-) WT骨髓嵌合小鼠比LT β(-/-)小鼠更具抗性，但与感染的WT小鼠相比，它们控制寄生虫的能力仍然降低，IL-12和ifn - γ的产生也存在缺陷。这些结果表明，膜淋巴蛋白通过促进T细胞介导的有效抗利什曼原虫免疫，在抵抗L. major中起关键作用。
Although the essential role of TNF-alpha in the control of intracellular pathogens including Leishmania major is well established, it is uncertain whether the related cytokine lymphotoxin alpha beta 2 (LT alpha 1 beta 2, membrane lymphotoxin) plays any role in this process. In this study, we investigated the contribution of membrane lymphotoxin in host response to L. major infection by using LT beta-deficient (LT beta(-/-)) mice on the resistant C57BL/6 background. Despite mounting early immune responses comparable to those of wild-type (WT) mice, LT beta(-/-) mice developed chronic nonhealing cutaneous lesions due to progressive and unresolving inflammation that is accompanied by uncontrolled parasite proliferation. This chronic disease was associated with striking reduction in IL-12 and Ag-specific IFN-gamma production by splenocytes from infected mice. Consistent with defective cellular immune response, infected LT beta(-/-) mice had significantly low Ag-specific serum IgG1 and IgG2a levels compared with WT mice. Although administration of rIL-12 to L. major-infected LT beta(-/-) mice caused complete resolution of chronic lesions, it only partially (but significantly) reduced parasite proliferation. In contrast, blockade of LIGHT signaling in infected LT beta(-/-) mice resulted in acute and progressive lesion development, massive parasite proliferation, and dissemination to the visceral organs. Although infected LT beta(-/-) WT bone marrow chimeric mice were more resistant than LT beta(-/-) mice, they still had reduced ability to control parasites and showed defective IL-12 and IFN-gamma production compared with infected WT mice. These results suggest that membrane lymphotoxin plays critical role in resistance to L. major by promoting effective T cell-mediated anti-Leishmania immunity.