Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Friedrich-Alexander-Universität Erlangen-Nürnberg, and Universitätsklinikum Erlangen, Erlangen, Germany .
Infect Immun. 2011 Jul;79(7):2699-708. doi: 10.1128/IAI.00079-11. Epub 2011 Apr 25.
Natural killer (NK) cells are important components of a protective immune response against intracellular pathogens such as Leishmania parasites, which reside within myeloid cells. Previous in vivo studies in murine cutaneous or visceral leishmaniasis showed that NK cells are activated by conventional dendritic cells in a Toll-like receptor 9-, interleukin-12 (IL-12)-, and IL-18-dependent manner during the early phase of infection and help to restrict the tissue parasite burden by unknown mechanisms. Here, we tested whether NK cells contribute to the control of Leishmania infections by lysing or by activating infected host cells. Coculture experiments revealed that activated NK cells from poly(I:C)-treated mice readily killed tumor target cells, whereas Leishmania infantum- or L. major-infected macrophages or dendritic cells remained viable. Infection with Leishmania did not significantly alter the expression of NK cell-activating molecules (retinoic acid early transcript alpha [Rae-1α], mouse UL16-binding protein-like transcript 1 [MULT-1], CD48) or inhibitory molecules (major histocompatibility complex [MHC] class I, nonclassical MHC class 1b molecule Qa-1) on the surface of myeloid cells, which offers an explanation for their protection from NK cell cytotoxicity. Consistent with these in vitro data, in vivo cytotoxicity assays revealed poor cytolytic activity of NK cells against adoptively transferred infected wild-type macrophages, whereas MHC class I-deficient macrophages were efficiently eliminated. NK cells activated by IL-12 and IL-18 stimulated macrophages to kill intracellular Leishmania in a cell contact-independent but gamma interferon-, tumor necrosis factor-, and inducible nitric oxide synthase-dependent manner. We conclude that Leishmania parasites, unlike viruses, do not render infected myeloid cells susceptible to the cytotoxicity of NK cells. Instead, soluble products of NK cells trigger the leishmanicidal activity of macrophages.
自然杀伤 (NK) 细胞是针对细胞内病原体（如利什曼原虫寄生虫）的保护性免疫反应的重要组成部分，这些病原体存在于髓样细胞内。先前在小鼠皮肤或内脏利什曼病的体内研究表明，NK 细胞在感染的早期阶段通过 Toll 样受体 9、白细胞介素-12 (IL-12) 和 IL-18 依赖的方式被常规树突状细胞激活，并通过未知机制帮助限制组织寄生虫负担。在这里，我们测试了 NK 细胞是否通过裂解或通过激活感染的宿主细胞来有助于控制利什曼虫感染。共培养实验表明，来自 poly(I:C) 处理的小鼠的活化 NK 细胞容易杀死肿瘤靶细胞，而利什曼原虫婴儿或 L. major 感染的巨噬细胞或树突状细胞仍然存活。感染利什曼原虫不会显著改变髓样细胞表面 NK 细胞激活分子（视黄酸早期转录物 alpha [Rae-1α]、鼠 UL16 结合蛋白样转录物 1 [MULT-1]、CD48）或抑制分子（主要组织相容性复合体 [MHC] 类 I、非经典 MHC 类 1b 分子 Qa-1）的表达，这为它们免受 NK 细胞细胞毒性提供了解释。与这些体外数据一致，体内细胞毒性测定显示 NK 细胞对过继转移感染的野生型巨噬细胞的细胞毒性活性差，而 MHC 类 I 缺陷型巨噬细胞则被有效消除。IL-12 和 IL-18 激活的 NK 细胞刺激巨噬细胞以非细胞接触方式但依赖于γ干扰素、肿瘤坏死因子和诱导型一氧化氮合酶杀死细胞内利什曼原虫。我们得出结论，与病毒不同，利什曼原虫寄生虫不会使感染的髓样细胞易受 NK 细胞的细胞毒性作用。相反，NK 细胞的可溶性产物触发巨噬细胞的杀利什曼原虫活性。
