Yap G S, Sher A
Immunobiology Section, Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Exp Med. 1999 Apr 5;189(7):1083-92. doi: 10.1084/jem.189.7.1083.
Although interferon (IFN)-gamma-activated, mononuclear phagocytes are considered to be the major effectors of resistance to intracellular pathogens, it is unclear how they control the growth of microorganisms that reside in nonhemopoietic cells. Pathogens within such cells may be killed by metabolites secreted by activated macrophages or, alternatively, directly controlled by cytokine-induced microbicidal mechanisms triggered within infected nonphagocytic cells. To distinguish between these two basic mechanisms of cell-mediated immunity, reciprocal bone marrow chimeras were constructed between wild-type and IFN-gamma receptor-deficient mice and their survival assessed following infection with Toxoplasma gondii, a protozoan parasite that invades both hemopoietic and nonhemopoietic cell lineages. Resistance to acute and persistent infection was displayed only by animals in which IFN-gamma receptors were expressed in both cellular compartments. Parallel chimera experiments performed with tumor necrosis factor (TNF) receptor-deficient mice also indicated a codependence on hemopoietic and nonhemopoietic lineages for optimal control of the parasite. In contrast, in mice chimeric for inducible nitric oxide synthase (iNOS), an enzyme associated with IFN-gamma-induced macrophage microbicidal activity, expression by cells of hemopoietic origin was sufficient for host resistance. Together, these findings suggest that, in concert with bone marrow-derived effectors, nonhemopoietic cells can directly mediate, in the absence of endogenous iNOS, IFN-gamma- and TNF-alpha-dependent host resistance to intracellular infection.
尽管干扰素（IFN）-γ激活的单核吞噬细胞被认为是抵抗细胞内病原体的主要效应细胞，但尚不清楚它们如何控制存在于非造血细胞中的微生物的生长。此类细胞内的病原体可能被活化巨噬细胞分泌的代谢产物杀死，或者由感染的非吞噬细胞内触发的细胞因子诱导的杀菌机制直接控制。为了区分细胞介导免疫的这两种基本机制，在野生型和IFN-γ受体缺陷型小鼠之间构建了相互骨髓嵌合体，并在感染刚地弓形虫（一种侵袭造血和非造血细胞谱系的原生动物寄生虫）后评估它们的存活情况。只有在两个细胞区室中均表达IFN-γ受体的动物才表现出对急性和持续性感染的抵抗力。用肿瘤坏死因子（TNF）受体缺陷型小鼠进行的平行嵌合体实验也表明，对寄生虫的最佳控制依赖于造血和非造血谱系。相比之下，在诱导型一氧化氮合酶（iNOS）嵌合的小鼠中，iNOS是一种与IFN-γ诱导的巨噬细胞杀菌活性相关的酶，造血来源细胞的表达足以使宿主产生抵抗力。总之，这些发现表明，与骨髓来源的效应细胞协同作用，非造血细胞可以在没有内源性iNOS的情况下直接介导IFN-γ和TNF-α依赖的宿主对细胞内感染的抵抗力。
