Human Leukocyte Antigens A*3001 and A*3002 Show Distinct Peptide-Binding Patterns of the Mycobacterium tuberculosis Protein TB10.4: Consequences for Immune Recognition
Human Leukocyte Antigens A*3001 and A*3002 Show Distinct Peptide-Binding Patterns of the Mycobacterium tuberculosis Protein TB10.4: Consequences for Immune Recognition
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DOI：
10.1128/cvi.00302-10
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发表时间：
2011-01-01
影响因子：
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通讯作者：
Maeurer, Markus
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文献类型：
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作者：
Axelsson-Robertson, Rebecca;Ahmed, Raija K.;Maeurer, Markus
结核病高负担国家位于撒哈拉以南非洲。我们检查了人类白细胞抗原（HLA）等位基因的频率，然后是最常见的HLA-A等位基因的重组表达，即，HLA-A*3001和HLA-A*3002，以研究分枝杆菌肽呈递和CD 8（+）T细胞识别的差异。我们筛选了一个肽库（9聚体肽与8个氨基酸重叠）的结合，亲和力，和解离率的结核分枝杆菌相关抗原TB10.4和确定只有三个TB10.4肽与相当大的结合HLA-A*3001。相比之下，22个肽结合HLA-A*3002。这反映了两个等位基因之间结合偏好的显著差异，A*3002耐受更混杂的肽结合模式，而A*3001仅容纳非常选择性的肽库。随后分析的亲和力和解离速率的结合肽揭示了一个强大的亲和力（8纳米至7 μ M）和中等解离速率（20分钟至3小时）的两个等位基因。构建含有来自TB10.4的选择的结合肽（包括在两个等位基因之间共享的肽QIMYNYPAM（TB10.4（3-11）的HLA-A*3001和HLA-A*3002四聚体，允许我们计数具有活动性TB的HLA-A*3001和HLA-A*3002型患者中的表位特异性T细胞。HLA-A*3001和HLA-A*3002主要组织相容性复合物-肽复合物在活动性TB个体中被识别，无论其纯合HLA-A*3001或HLA-A*3002遗传背景如何。抗原特异性T细胞表现出CD 45 RA（+）CCR 7（+）前体表型和白细胞介素-7受体（CD 127），这与亲本CD 8（+）T细胞群体表现出的表型和受体不同。
High-tuberculosis (TB)-burden countries are located in sub-Saharan Africa. We examined the frequency of human leukocyte antigen (HLA) alleles, followed by recombinant expression of the most frequent HLA-A alleles, i.e., HLA-A*3001 and HLA-A*3002, to study differences in mycobacterial peptide presentation and CD8(+) T-cell recognition. We screened a peptide library (9-mer peptides with an 8-amino-acid overlap) for binding, affinity, and off-rate of the Mycobacterium tuberculosis-associated antigen TB10.4 and identified only three TB10.4 peptides with considerable binding to HLA-A*3001. In contrast, 22 peptides bound to HLA-A*3002. This reflects a marked difference in the binding preference between the two alleles, with A*3002 tolerating a more promiscuous peptide-binding pattern and A*3001 accommodating only a very selective peptide repertoire. Subsequent analysis of the affinity and off-rate of the binding peptides revealed a strong affinity (8 nM to 7 mu M) and moderate off-rate (20 min to 3 h) for both alleles. Construction of HLA-A*3001 and HLA-A*3002 tetramers containing selected binding peptides from TB10.4, including a peptide which was shared among both alleles, QIMYNYPAM (TB10.4(3-11)), allowed us to enumerate epitope-specific T cells in HLA-A*3001-and HLA-A*3002-typed patients with active TB. HLA-A*3001 and HLA-A*3002 major histocompatibility complex-peptide complexes were recognized in individuals with active TB, irrespective of their homozygous HLA-A*3001 or HLA-A*3002 genetic background. The antigen-specific T cells exhibited the CD45RA(+) CCR7(+) precursor phenotype and the interleukin-7 receptor (CD127), which were different from the phenotype and receptor exhibited by the parental CD8(+) T-cell population.