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首页> 外文期刊>The Journal of Immunology: Official Journal of the American Association of Immunologists >Identification of major epitopes of Mycobacterium tuberculosis AG85B that are recognized by HLA-A*0201-restricted CD8+ T cells in HLA-transgenic mice and humans.
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Identification of major epitopes of Mycobacterium tuberculosis AG85B that are recognized by HLA-A*0201-restricted CD8+ T cells in HLA-transgenic mice and humans.

机译：鉴定结核分枝杆菌AG85B的主要表位，这些表位可在HLA转基因小鼠和人类中被HLA-A * 0201限制的CD8 + T细胞识别。

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摘要

CD8(+) T cells are thought to play an important role in protective immunity to tuberculosis. Although several nonprotein ligands have been identified for CD1-restricted CD8(+) CTLs, epitopes for classical MHC class I-restricted CD8(+) T cells, which most likely represent a majority among CD8(+) T cells, have remained ill defined. HLA-A*0201 is one of the most prevalent class I alleles, with a frequency of over 30% in most populations. HLA-A2/K(b) transgenic mice were shown to provide a powerful model for studying induction of HLA-A*0201-restricted immune responses in vivo. The Ag85 complex, a major component of secreted Mycobacterium tuberculosis proteins, induces strong CD4(+) T cell responses in M. tuberculosis-infected individuals, and protection against tuberculosis in Ag85-DNA-immunized animals. In this study, we demonstrate the presence of HLA class I-restricted, CD8(+) T cells against Ag85B of M. tuberculosis in HLA-A2/K(b) transgenic mice and HLA-A*0201(+) humans. Moreover, two immunodominant Ag85 peptide epitopes for HLA-A*0201-restricted, M. tuberculosis-reactive CD8(+) CTLs were identified. These CD8(+) T cells produced IFN-gamma and TNF-alpha and recognized Ag-pulsed or bacillus Calmette-Guerin-infected, HLA-A*0201-positive, but not HLA-A*0201-negative or uninfected human macrophages. This CTL-mediated killing was blocked by anti-CD8 or anti-HLA class I mAb. Using fluorescent peptide/HLA-A*0201 tetramers, Ag85-specific CD8(+) T cells could be visualized in bacillus Calmette-Guerin-responsive, HLA-A*0201(+) individuals. Collectively, our results demonstrate the presence of HLA class I-restricted CD8(+) CTL against a major Ag of M. tuberculosis and identify Ag85B epitopes that are strongly recognized by HLA-A*0201-restricted CD8(+) T cells in humans and mice. These epitopes thus represent potential subunit components for the design of vaccines against tuberculosis.
机译：CD8（+）T细胞被认为在结核病的保护性免疫中起着重要作用。尽管已为CD1限制性CD8（+）CTL鉴定了几种非蛋白质配体，但经典的MHC I类限制性CD8（+）T细胞（最有可能代表CD8（+）T细胞中的大多数）的表位仍然不确定。 HLA-A * 0201是最流行的I类等位基因之一，在大多数人群中的频率超过30％。显示HLA-A2 / K（b）转基因小鼠为研究体内诱导HLA-A * 0201限制的免疫反应提供了强大的模型。 Ag85复合物是分泌型结核分枝杆菌蛋白的主要成分，可在结核分枝杆菌感染的个体中诱导强烈的CD4（+）T细胞反应，并在经Ag85-DNA免疫的动物中预防结核病。在这项研究中，我们证明了HLA-I2 / K（b）转基因小鼠和HLA-A * 0201（+）人类中存在HLA I类限制性CD8（+）T细胞对抗结核分枝杆菌Ag85B。此外，针对HLA-A * 0201限制的结核分枝杆菌反应性CD8（+）CTL，鉴定了两个免疫优势的Ag85肽表位。这些CD8（+）T细胞产生IFN-γ和TNF-α，并识别受Ag脉冲或卡介苗感染的HLA-A * 0201阳性，但未检测到HLA-A * 0201阴性或未感染的人类巨噬细胞。这种CTL介导的杀伤作用被抗CD8或抗HLA I类单克隆抗体阻断。使用荧光肽/ HLA-A * 0201四聚体，可以在卡介苗-Guerin应答的HLA-A * 0201（+）个体中观察到Ag85特异性CD8（+）T细胞。总的来说，我们的结果表明存在针对人类结核分枝杆菌主要抗原的HLA I类限制性CD8（+）CTL，并鉴定了人类中HLA-A * 0201限制性CD8（+）T细胞强烈识别的Ag85B表位和老鼠。因此，这些表位代表用于设计抗结核疫苗的潜在亚基成分。

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