Immunodominant tuberculosis CD8 antigens preferentially restricted by HLA-B.
Immunodominant tuberculosis CD8 antigens preferentially restricted by HLA-B.
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DOI：
10.1371/journal.ppat.0030127
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发表时间：
2007-09-21
期刊：
影响因子：
6.7
通讯作者：
Lewinsohn, David M
中科院分区：
文献类型：
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作者：
Lewinsohn, Deborah A;Winata, Ervina;Swarbrick, Gwendolyn M;Tanner, Katie E;Cook, Matthew S;Null, Megan D;Cansler, Meghan E;Sette, Alessandro;Sidney, John;Lewinsohn, David M
CD 8 + T细胞对于宿主防御胞内细菌病原体如结核分枝杆菌（Mtb）、沙门氏菌属和单核细胞增生李斯特菌是必不可少的，但这些病原体的人CD 8抗原的库和优势模式仍然缺乏表征。结核病（TB）是由Mtb感染引起的疾病，仍然是全世界感染性发病率和死亡率的主要原因之一，并且是HIV/AIDS患者中最常见的机会性感染。因此，我们进行了这项研究，以确定免疫显性CD 8 Mtb抗原。首先，使用IFN-γ ELISPOT和合成肽阵列作为抗原来源，我们测量了潜伏性结核感染者中识别已知免疫显性CD 4 + T细胞抗原的CD 8 + T细胞的离体频率。此外，使用有限稀释来产生Mtb特异性T细胞克隆组。使用肽阵列，我们确定了大多数T细胞克隆的抗原特异性，定义了几个新的表位。在所有情况下，代表最小表位的肽以高亲和力结合至主要组织相容性复合体（MHC）限制性等位基因，并且在除一种情况之外的所有情况下，限制性等位基因是HLA-B等位基因。此外，从其分离T细胞克隆的个体具有对表位特异的高离体频率的CD 8 + T细胞应答，并且在测试的个体中，表位代表CD 8抗原内的单一免疫显性应答。我们的结论是，结核分枝杆菌特异性CD 8 + T细胞被发现在感染的个体中的高频率，并主要由HLA-B等位基因的限制，合成肽阵列可用于定义表位特异性，而无需事先偏见的MHC结合亲和力。这些发现提供了对人类免疫优势的更好理解，并可能有助于开发有效的结核病疫苗和改进免疫诊断。CD 8 + T细胞对于宿主防御胞内细菌病原体如结核分枝杆菌（Mtb）、沙门氏菌属和单核细胞增生李斯特菌是必需的，然而关于人类CD 8 + T细胞响应于结核（TB）而识别的抗原知之甚少。结核病是由结核分枝杆菌感染引起的疾病，仍然是全世界疾病和死亡的主要原因之一，并且是艾滋病毒/艾滋病患者中常见的并发感染。因此，我们进行了这项研究，以确定公认的CD 8 Mtb抗原。首先，我们测量了识别Mtb抗原的CD 8 + T细胞的频率，已知Mtb抗原在感染Mtb的人中被CD 4 + T细胞抗原识别。此外，我们确定了Mtb抗原和表位识别的几个CD 8 + T细胞克隆分离感染的个人。除了一种情况外，所有的表位都由HLA-B等位基因呈递给T细胞克隆。我们得出结论，结核分枝杆菌特异性CD 8 + T细胞被发现在感染的个体中的高频率，并主要由HLA-B等位基因的限制。这些发现提供了对人类免疫系统如何识别细胞内病原体的更好理解，并可能有助于开发有效的结核病疫苗和改进的免疫诊断。
CD8+ T cells are essential for host defense to intracellular bacterial pathogens such as Mycobacterium tuberculosis (Mtb), Salmonella species, and Listeria monocytogenes, yet the repertoire and dominance pattern of human CD8 antigens for these pathogens remains poorly characterized. Tuberculosis (TB), the disease caused by Mtb infection, remains one of the leading causes of infectious morbidity and mortality worldwide and is the most frequent opportunistic infection in individuals with HIV/AIDS. Therefore, we undertook this study to define immunodominant CD8 Mtb antigens. First, using IFN-γ ELISPOT and synthetic peptide arrays as a source of antigen, we measured ex vivo frequencies of CD8+ T cells recognizing known immunodominant CD4+ T cell antigens in persons with latent tuberculosis infection. In addition, limiting dilution was used to generate panels of Mtb-specific T cell clones. Using the peptide arrays, we identified the antigenic specificity of the majority of T cell clones, defining several new epitopes. In all cases, peptide representing the minimal epitope bound to the major histocompatibility complex (MHC)-restricting allele with high affinity, and in all but one case the restricting allele was an HLA-B allele. Furthermore, individuals from whom the T cell clone was isolated harbored high ex vivo frequency CD8+ T cell responses specific for the epitope, and in individuals tested, the epitope represented the single immunodominant response within the CD8 antigen. We conclude that Mtb-specific CD8+ T cells are found in high frequency in infected individuals and are restricted predominantly by HLA-B alleles, and that synthetic peptide arrays can be used to define epitope specificities without prior bias as to MHC binding affinity. These findings provide an improved understanding of immunodominance in humans and may contribute to a development of an effective TB vaccine and improved immunodiagnostics. CD8+ T cells are essential for host defense to intracellular bacterial pathogens such as Mycobacterium tuberculosis (Mtb), Salmonella species, and Listeria monocytogenes, yet little is known about the antigens recognized by human CD8+ T cells in response to tuberculosis (TB). TB, the disease caused by Mtb infection, remains one of the leading causes of illness and death worldwide and is a frequent complicating infection in individuals with HIV/AIDS. Therefore, we undertook this study to define commonly recognized CD8 Mtb antigens. First, we measured the frequencies of CD8+ T cells recognizing Mtb antigens known to be recognized by CD4+ T cell antigens in persons infected with Mtb. In addition, we identified the Mtb antigen and epitope recognized by several CD8+ T cell clones isolated from infected individuals. The epitope was presented to the T cell clones by an HLA-B allele in all but one case. We conclude that Mtb-specific CD8+ T cells are found in high frequency in infected individuals and are restricted predominantly by HLA-B alleles. These findings provide an improved understanding of how the human immune system recognizes intracellular pathogens and may contribute to the development of an effective TB vaccine and improved immunodiagnostics.