Memory T cells in latent Mycobacterium tuberculosis infection are directed against three antigenic islands and largely contained in a CXCR3+CCR6+ Th1 subset.
Memory T cells in latent Mycobacterium tuberculosis infection are directed against three antigenic islands and largely contained in a CXCR3+CCR6+ Th1 subset.
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DOI：
10.1371/journal.ppat.1003130
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Sette A
中科院分区：
文献类型：
--
作者：
Lindestam Arlehamn CS;Gerasimova A;Mele F;Henderson R;Swann J;Greenbaum JA;Kim Y;Sidney J;James EA;Taplitz R;McKinney DM;Kwok WW;Grey H;Sallusto F;Peters B;Sette A
对结核分枝杆菌（MTB） CD4 T细胞识别的免疫学足迹的理解仍然不完整。在这里，我们报告了MTB特异性的人类Th1细胞主要包含在CXCR3+CCR6+记忆亚群中，并且高度集中在三个广泛免疫优势的抗原岛上，这些岛都与细菌分泌系统有关。我们的研究结果反驳了分泌抗原作为诱饵的观点，因为分泌蛋白和组成分泌系统本身的蛋白质都是功能齐全的T细胞反应的目标。此外，还发现了几种新的T细胞抗原，可作为潜在的诊断用途，或作为疫苗抗原。这些结果强调了基于表位预测、高通量ELISPOT和使用来自潜伏MTB感染个体的pbmc的T细胞文库的综合使用，对CD4 MTB识别进行真正无偏见的全基因组分析的力量。结核分枝杆菌是有史以来最威胁生命的病原体之一，目前感染了三分之一的人口。迫切需要新的疫苗和诊断策略。在这里，我们能够确定潜伏感染个体最主要识别的目标，并成功地控制感染。这些靶点包含在三个广泛的基因组抗原岛中，它们都与细菌分泌系统有关，并由几个不同的orf组成。因此，我们的研究结果表明，接种一种或几种确定的抗原将无法复制与自然免疫相关的反应。我们的分析还指出，主导应答的Th1细胞与新的、明确的表型标记有关，这表明应答是由独特的MTB相关因素塑造的。该研究进一步表明，将多肽结合预测与现代高通量技术相结合的方法普遍适用于对其他复杂病原体的免疫研究。总之，我们的数据为全球抗击结核分枝杆菌提供了一个新的角度，并可用于诊断或疫苗开发。
An understanding of the immunological footprint of Mycobacterium tuberculosis (MTB) CD4 T cell recognition is still incomplete. Here we report that human Th1 cells specific for MTB are largely contained in a CXCR3+CCR6+ memory subset and highly focused on three broadly immunodominant antigenic islands, all related to bacterial secretion systems. Our results refute the notion that secreted antigens act as a decoy, since both secreted proteins and proteins comprising the secretion system itself are targeted by a fully functional T cell response. In addition, several novel T cell antigens were identified which can be of potential diagnostic use, or as vaccine antigens. These results underline the power of a truly unbiased, genome-wide, analysis of CD4 MTB recognition based on the combined use of epitope predictions, high throughput ELISPOT, and T cell libraries using PBMCs from individuals latently infected with MTB. Mycobacterium tuberculosis is one of the most life-threatening pathogens of all time, having infected one-third of the present human population. There is an urgent need for both novel vaccines and diagnostic strategies. Here, we were able to identify the targets most dominantly recognized by latently infected individual that successfully contain infection. These targets are contained in three broadly genomic antigenic islands, all related to bacterial secretion systems and composed by several distinct ORFs. Thus, our results suggest that vaccination with one or few defined antigens will fail to replicate the response associated with natural immunity. Our analysis also pinpoints that the Th1 cells dominating the response are associated with novel and well-defined phenotypic markers, suggesting that the response is molded by unique MTB associated factors. This study demonstrates further that the approach combining peptide binding predictions with modern high throughput techniques is generally applicable to the study of immunity to other complex pathogens. Together, our data provide a new angle in the worldwide fight against M. tuberculosis and could be used for diagnostic or vaccine developments.
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DOI：
10.4049/jimmunol.1103556
发表时间：
2012-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Arlehamn CS;Sidney J;Henderson R;Greenbaum JA;James EA;Moutaftsi M;Coler R;McKinney DM;Park D;Taplitz R;Kwok WW;Grey H;Peters B;Sette A
通讯作者：
Sette A
影响因子：
4.4
作者：
Caccamo, Nadia;Meraviglia, Serena;Salerno, Alfredo
通讯作者：
Salerno, Alfredo
影响因子：
3.1
作者：
HAVLIR, DV;WALLIS, RS;ELLNER, JJ
通讯作者：
ELLNER, JJ
影响因子：
30.5
作者：
Duhen, Thomas;Geiger, Rebekka;Sallusto, Federica
通讯作者：
Sallusto, Federica
影响因子：
5.4
作者：
Beveridge, Natalie E. R.;Price, David A.;McShane, Helen
通讯作者：
McShane, Helen