Contributions of IFN-γ and granulysin to the clearance ofPlasmodium yoeliiblood stage
Contributions of IFN-γ and granulysin to the clearance ofPlasmodium yoeliiblood stage
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DOI：
10.1371/journal.ppat.1008840
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发表时间：
2020-09-01
期刊：
影响因子：
6.7
通讯作者：
Gazzinelli, Ricardo Tostes
中科院分区：
文献类型：
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作者：
Hojo-Souza, Natalia Satchiko;de Azevedo, Patrick Orestes;Gazzinelli, Ricardo Tostes
间日疟原虫感染的Retics（iRetics）表达人类白细胞抗原I类（HLA-I），被CD 8（+）T细胞识别，并被颗粒溶素（GNLY）和颗粒酶杀死。然而，疟原虫感染如何诱导Retics上MHC-I表达尚不清楚。此外，GNLY是否有助于控制体内疟原虫感染还没有研究。在这里，我们研究这些问题使用啮齿动物感染约氏疟原虫17 XNL株，其中有Retics的向性。约氏疟原虫感染导致髓外红细胞生成、网织红细胞增多以及产生CD 8（+）CD 44（+）CD 62 L（-）IFN-γ的T细胞的扩增，这些T细胞与iRetics形成免疫突触。我们现在提供的证据表明，iRetic的MHC-I表达依赖于IFN-γ诱导的成红细胞中IRF-1、MHC-I和β 2-微球蛋白（β 2-m）的转录。一致地，来自感染的野生型（WT）小鼠的CTL以IFN-γ和MHC-I依赖性方式与iRetics形成免疫突触。当用约氏疟原虫17 XNL攻击时，WT小鼠清除了寄生虫血症并存活，而IFN-γ KO小鼠仍然寄生虫血症并全部死亡。不表达MHC-I且几乎没有CD 8（+）T细胞的β 2-m KO小鼠具有延长的寄生虫血症，并且80%存活。由于小鼠不表达GNLY，因此GNLY转基因小鼠可用于评估GNLY的体内重要性。GNLY转基因小鼠的寄生虫清除加速，CD 8（+）T细胞的耗竭消除了GNLY介导的对约氏疟原虫的抗性。总之，我们的结果表明，除了先前描述的机制，IFN-γ通过促进iRetics上的MHC-I表达来促进宿主对Retic-tropicP.约氏疟原虫17 XNL株的抗性，iRetics成为CD 8（+）细胞毒性T淋巴细胞和GNLY的靶点。肿瘤监测。识别由有核细胞中表达的MHC-I分子呈递的肽表位的CTL被激活，并通过将细胞毒性颗粒的内容物释放到免疫突触中来杀死感染的靶细胞。由于大多数疟原虫属（Plasmodium spp.）感染去核且不表达MHC-I的红细胞时，CD 8（+）T细胞在疟疾的血液阶段中的作用被忽视。我们最近发现间日疟原虫感染的网织红细胞表达MHC-I，并以依赖于颗粒溶解素（GNLY）的方式被杀死，GNLY是一种细胞毒性颗粒效应蛋白。然而，CD 8（+）T细胞的保护作用是有争议的，GNL在体内的作用仍有待证实。在这里，我们发现CTL和GNLY介导小鼠对约氏疟原虫血液阶段感染的抵抗力，约氏疟原虫是一种啮齿类疟原虫，优选感染网织红细胞。
P.vivax-infected Retics (iRetics) express human leukocyte antigen class I (HLA-I), are recognized by CD8(+)T cells and killed by granulysin (GNLY) and granzymes. However, howPlasmodiuminfection induces MHC-I expression on Retics is unknown. In addition, whether GNLY helps controlPlasmodiuminfectionin vivohas not been studied. Here, we examine these questions using rodent infection with theP.yoelii17XNL strain, which has tropism for Retics. Infection withP.yoeliicaused extramedullary erythropoiesis, reticulocytosis and expansion of CD8(+)CD44(+)CD62L(-)IFN-gamma-producing T cells that form immune synapses with iRetics. We now provide evidence that MHC-I expression by iRetic is dependent on IFN-gamma-induced transcription of IRF-1, MHC-I and beta 2-microglobulin (beta 2-m) in erythroblasts. Consistently, CTLs from infected wild type (WT) mice formed immune synapses with iRetics in an IFN-gamma- and MHC-I-dependent manner. When challenged withP.yoelii17XNL, WT mice cleared parasitemia and survived, while IFN-gamma KO mice remained parasitemic and all died. beta 2-m KO mice that do not express MHC-I and have virtually no CD8(+)T cells had prolonged parasitemia, and 80% survived. Because mice do not express GNLY,GNLY-transgenic mice can be used to assess thein vivoimportance of GNLY. Parasite clearance was accelerated inGNLY-transgenic mice and depletion of CD8(+)T cells ablated the GNLY-mediated resistance toP.yoelii. Altogether, our results indicate that in addition to previously described mechanisms, IFN-gamma promotes host resistance to the Retic-tropicP.yoelii17XNL strain by promoting MHC-I expression on iRetics that become targets for CD8(+)cytotoxic T lymphocytes and GNLY.Author summary CD8(+)cytotoxic T lymphocytes (CTLs) are important for immune defense against intracellular pathogens, such as viruses, bacteria and parasites, and tumor surveillance. CTLs, which recognize peptide epitopes presented by MHC-I molecules expressed in nucleated cells, become activated and kill infected target cells by releasing the contents of cytotoxic granules into the immunological synapse. Since mostPlasmodium spp. infect erythrocytes that are enucleated and do not express MHC-I, the role of CD8(+)T cells in the blood-stage of malaria has been neglected. We recently showed thatP.vivax-infected reticulocytes express MHC-I and are killed in a manner dependent on granulysin (GNLY), a cytotoxic granule effector protein. However, the protective role of CD8(+)T cells is controversial and the role of GNLYin vivoremains to be demonstrated. Here, we show that CTLs and GNLY mediate mouse resistance to blood-stage infection withP.yoelii, a rodent malaria parasite that preferably infects reticulocytes.