Weichold F F, Mueller S, Kortsik C, Hitzler W E, Wulf M J, Hone D M, Sadoff J C, Maeurer M J
Aeras Global TB Vaccine Foundation, Bethesda, MD, USA.
Genes Immun. 2007 Jun;8(4):334-43. doi: 10.1038/sj.gene.6364392. Epub 2007 Apr 12.
Challenged by scattered understanding of protective immunity to Mycobacterium tuberculosis (MTB), we have mapped peptide epitopes to human leukocyte antigen (HLA)-A0101, A0201, A1101, A2402, B0702, B0801 and B1501 of the secreted mycobacterial antigen Ag85B, a vaccine candidate that may be associated with immune protection. Affinity (ED(50)) and half-life (t(1/2), off-rate) analysis for individual peptide species on HLA-A and HLA-B molecules revealed binding ranges between 10(-3) and 10(-7) M. After selection of the best matches, major histocompatibility complex class I/peptide tetramer complexes were constructed to measure the CD8+ T-cell responses directly ex vivo in peripheral blood mononuclear cells (PBMC) derived from 57 patients with acute pulmonary tuberculosis. Three patterns of (allele-) specific CD8+ recognition were identified: (a). Focus on one dominant epitope with additional recognition of several subdominant T-cell epitopes (HLA-A0301, A2402, B0801 and B1501); (b). Co-dominant recognition of two distinct groups of peptides presented by HLA-B0702; and (c). Diverse and broad recognition of peptides presented by HLA-A0201. Peptides that bound with slow off-rates to class I alleles, that is HLA-A0201, were associated with low frequency of CD8+ T cells in PBMCs from patients with tuberculosis. HLA-B alleles showed fast off-rates in peptide binding and restricted high numbers (up to 6%) of antigen-specific CD8+ T cells in patients with pulmonary tuberculosis.
由于对结核分枝杆菌（MTB）保护性免疫的认识零散，我们已将分泌型分枝杆菌抗原Ag85B（一种可能与免疫保护相关的候选疫苗）的肽表位映射到人类白细胞抗原（HLA）-A0101、A0201、A1101、A2402、B0702、B0801和B1501。对HLA-A和HLA-B分子上单个肽种类的亲和力（ED(50)）和半衰期（t(1/2)，解离速率）分析显示结合范围在10^(-3)至10^(-7) M之间。选择最佳匹配肽后，构建了主要组织相容性复合体I类/肽四聚体复合物，以直接在体外测量来自57例急性肺结核患者外周血单核细胞（PBMC）中的CD8+ T细胞反应。确定了三种（等位基因）特异性CD8+识别模式：（a）聚焦于一个显性表位，并额外识别几个亚显性T细胞表位（HLA-A0301、A2402、B0801和B1501）；（b）由HLA-B0702呈递的两组不同肽的共显性识别；（c）对由HLA-A0201呈递的肽的多样且广泛的识别。与I类等位基因（即HLA-A0201）结合解离速率慢的肽，与肺结核患者PBMC中低频的CD8+ T细胞相关。HLA-B等位基因在肽结合中显示出快速解离速率，并在肺结核患者中限制出现大量（高达6%）抗原特异性CD8+ T细胞。
