MHC class II tetramer guided detection of Mycobacterium tuberculosis-specific CD4+ T cells in peripheral blood from patients with pulmonary tuberculosis
MHC class II tetramer guided detection of Mycobacterium tuberculosis-specific CD4+ T cells in peripheral blood from patients with pulmonary tuberculosis
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DOI：
10.1111/j.1365-3083.2007.01924.x
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发表时间：
2007-05-01
影响因子：
3.7
通讯作者：
Maeurer, M.
中科院分区：
文献类型：
--
作者：
Hoehn, H.;Kortsik, C.;Maeurer, M.
需要新的诊断工具来诊断潜伏感染并提供生物学上有意义的替代标记物来定义针对结核分枝杆菌（MTB）的细胞免疫应答。除了已有100多年历史的结核菌素皮肤试验（TST）外，最近还开发了基于干扰素γ的测定法，用于血液中MTB的免疫诊断。可溶性MHC/肽四聚体分子的出现允许客观地计数抗原特异性T细胞。我们鉴定了新的MHC II类限制性MTB表位，并使用HLA-DR 4四聚体复合物来体外观察针对抗原Ag 85 B和19-kDa脂蛋白的CD 4（+）T细胞，这些抗原在MTB和其他分枝杆菌物种之间共享，以及识别MTB相关ESAT-6抗原的CD 4（+）T细胞。MTB反应性CD 4（+）T细胞主要存在于CD 45 RA（+）CD 28（+）和CD 45（-）CD 28（+）T细胞亚群中，并识别天然加工和呈递的MTB表位。在患有肺MTB感染和随后成功治疗的患者中，当与针对相应的HLA-A2呈递的MTB表位的CD 8（+）T细胞相比时，HLA-DR 4限制性、Ag 85 B或ESAT-6特异性CD 4（+）T细胞在外周血单核细胞（PBMC）中随时间推移显示出相似的动力学。针对19-kDa脂蛋白的T细胞应答并未发现这一点。对M.结核病感染将使监测结核病疫苗候选者和测量针对结核病的CD 4（+）T细胞的新策略成为可能。
Novel diagnostic tools are needed to diagnose latent infection and to provide biologically meaningful surrogate markers to define cellular immune responses against Mycobacterium tuberculosis (MTB). Interferon gamma-based assays have recently been developed in addition to the more than 100-year-old tuberculin skin test (TST) for the immune diagnosis of MTB in blood. The advent of soluble MHC/peptide tetramer molecules allows to objectively enumerate antigen-specific T cells. We identified novel MHC class II-restricted MTB epitopes and used HLA-DR4 tetrameric complexes to visualize ex vivo CD4(+) T cells directed against the antigens Ag85B and the 19-kDa lipoprotein, shared between MTB and other Mycobacterium species, and CD4(+) T cells which recognize the MTB-associated ESAT-6 antigen. MTB-reactive CD4(+) T cells reside predominantly in the CD45RA(+) CD28(+) and CD45(-) CD28(+) T-cell subset and recognize naturally processed and presented MTB epitopes. HLA-DR4-restricted, Ag85B or ESAT-6-specific CD4(+) T cells show similar dynamics over time in peripheral blood mononuclear cells (PBMC) when compared with CD8(+) T cells directed against the corresponding HLA-A2-presented MTB epitopes in patients with pulmonary MTB infection and subsequent successful therapy. This was not found to be true for T-cell responses directed against the 19-kDa lipoprotein. The dissection of the cellular immune response in M. tuberculosis infection will enable novel strategies for monitoring MTB vaccine candidates and to gauge CD4(+) T cells directed against MTB.