Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
PLoS Pathog. 2010 Feb 26;6(2):e1000782. doi: 10.1371/journal.ppat.1000782.
Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA-E. We observed CD8(+) T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8(+) T-cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8(+) T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-beta. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8(+) T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity.
结核病（TB）是一个日益严重的全球健康问题，迫切需要改进的结核病疫苗。由于 HLA-E 显示出非常有限的多态性（仅存在 2 种编码变异），并且不受 HIV 感染下调，因此 HLA-E 限制的反应可能对疫苗开发感兴趣。然而，由结核分枝杆菌（Mtb）产生的潜在与 HLA-E 结合的肽是未知的。在这里，我们描述了人类 T 细胞对含有预测 HLA-E 结合基序和与 HLA-E 结合亲和力的 Mtb 衍生肽的反应。我们观察到大多数 69 种肽在 Mtb 反应性成年人以及 BCG 接种婴儿中均引起 CD8(+)T 细胞增殖。只有在存在特异性肽的情况下，CD8(+)T 细胞才会针对转染 HLA-E 的靶细胞进行细胞毒性。这些 T 细胞还能够裂解感染 M. bovis BCG 的但不是对照单核细胞的细胞，表明在分枝杆菌感染期间识别抗原。此外，肽诱导的 CD8(+)T 细胞还显示出调节活性，因为它们抑制 T 细胞增殖。这种调节活性是细胞接触依赖性的，至少部分依赖于膜结合的 TGF-β。我们的结果通过鉴定对 Mtb 的新型 HLA-E 结合肽具有细胞毒性和免疫调节活性的 CD8(+)T 细胞反应，显著提高了我们对人类对 Mtb 免疫反应的理解。
