Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity.
Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity.
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DOI：
10.1371/journal.ppat.1000782
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发表时间：
2010-02-26
期刊：
影响因子：
6.7
通讯作者：
Ottenhoff TH
中科院分区：
文献类型：
--
作者：
Joosten SA;van Meijgaarden KE;van Weeren PC;Kazi F;Geluk A;Savage ND;Drijfhout JW;Flower DR;Hanekom WA;Klein MR;Ottenhoff TH
结核病 (TB) 是一个不断升级的全球健康问题，迫切需要改进的结核病疫苗。 HLA-E 限制性反应可能对疫苗开发感兴趣，因为 HLA-E 显示出非常有限的多态性（仅存在 2 个编码变体），并且不会因 HIV 感染而下调。然而，HLA-E 分子可能呈递的来自结核分枝杆菌 (Mtb) 的肽尚不清楚。在这里，我们描述了人类 T 细胞对含有预测的 HLA-E 结合基序和 HLA-E 结合亲和力的 Mtb 衍生肽的反应。我们在 Mtb 反应性成人以及接种 BCG 的婴儿中观察到 CD8+ T 细胞对大多数测试的 69 种肽的增殖。仅在特定肽存在的情况下，CD8+ T 细胞才对 HLA-E 转染的靶细胞具有细胞毒性。这些T细胞还能够裂解被BCG感染的牛分枝杆菌，但不能裂解控制单核细胞，这表明在分枝杆菌感染期间能够识别抗原。此外，肽诱导的 CD8+ T 细胞还表现出调节活性，因为它们抑制 T 细胞增殖。这种调节活性依赖于细胞接触，并且至少部分依赖于膜结合的 TGF-β。我们的研究结果通过鉴定 CD8+ T 细胞对 Mtb 新型 HLA-E 结合肽的反应，显着增加了我们对人类对 Mtb 免疫反应的理解，该肽具有细胞毒性和免疫调节活性。 结核分枝杆菌 (Mtb) 感染了世界约三分之一的人口，每年导致 150 万人患上致命的肺结核 (TB)。结核分枝杆菌疫苗接种可以降低幼儿的发病率，但不能预防成人的肺结核。针对 Mtb 的免疫反应由多个参与者组成，其中之一是 CD8+ T 细胞。 CD8+ T 细胞识别受感染的细胞，因为 Mtb 衍生肽呈递在 HLA I 类分子上。在这里，我们研究了作为 Mtb 抗原递呈者的非经典 HLA 分子 HLA-E。 Mtb 基因组包含多个可由人类 HLA-E 呈递的序列。这些肽被对 Mtb 敏感的健康个体的 CD8+ T 细胞识别，导致 CD8+ T 细胞增殖。这些 T 细胞以 HLA-E 限制方式裂解分枝杆菌感染的细胞。此外，这些 T 细胞还抑制其附近其他 T 细胞的增殖，这是调节性 T 细胞的特性。这些 T 细胞的双重功能使它们在感染期间成为有趣的参与者，可能会根据环境平衡其功能。这些发现有助于我们了解结核分枝杆菌的免疫反应，并将有助于设计新的和改进的结核病疫苗。
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-β. 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. Mycobacterium tuberculosis (Mtb) has infected about one-third of the world population, resulting in fatal pulmonary tuberculosis (TB) in 1.5 million people annually. Vaccination against Mtb has decreased disease incidence in young children but does not prevent pulmonary TB in adults. The immune response against Mtb comprises multiple players, one of which is the CD8+ T-cell. CD8+ T-cells recognize infected cells because Mtb derived peptides are presented on HLA class I molecules. Here, we studied the non-classical HLA molecule HLA-E as presenter of Mtb antigens. The Mtb genome contained multiple sequences that can be presented by human HLA-E. These peptides were recognized by CD8+ T-cells from healthy individuals that were sensitized to Mtb, resulting in CD8+ T-cell proliferation. These T-cells lysed mycobacterium infected cells in a HLA-E restricted manner. Additionally, these T-cells also inhibited proliferation of other T-cells in their vicinity, a property of regulatory T-cells. The dual functionality of these T-cells makes them interesting players during infection, probably balancing their function depending on the environment. These findings contribute to our understanding of the immune response towards Mtb and will be helpful in designing new and improved vaccines against TB.
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MTB衍生的抗原对人CD8+ T细胞的HLA-E依赖性表现。
影响因子：
15.3
作者：
Heinzel, Amy S;Grotzke, Jeff E;Lines, Rebecca A;Lewinsohn, Deborah A;McNabb, Andria L;Streblow, Daniel N;Braud, Veronique M;Grieser, Heather J;Belisle, John T;Lewinsohn, David M
通讯作者：
Lewinsohn, David M
影响因子：
3.7
作者：
Caccamo N;Guggino G;Meraviglia S;Gelsomino G;Di Carlo P;Titone L;Bocchino M;Galati D;Matarese A;Nouta J;Klein MR;Salerno A;Sanduzzi A;Dieli F;Ottenhoff TH
通讯作者：
Ottenhoff TH
DOI：
10.1164/rccm.200508-1294oc
发表时间：
2006-04-01
影响因子：
24.7
作者：
Guyot-Revol, V;Innes, JA;Lalvani, A
通讯作者：
Lalvani, A
影响因子：
30.5
作者：
Hoare, HL;Sullivan, LC;Brooks, AG
通讯作者：
Brooks, AG
影响因子：
32.4
作者：
Cohen, GB;Gandhi, RT;Baltimore, D
通讯作者：
Baltimore, D