HLA-E restricted T-cell immunity in Mycobacterium tuberculosis infection

HLA-E 限制结核分枝杆菌感染中的 T 细胞免疫

基本信息

批准号：
10471834
负责人：
Simone Anne Joosten
金额：
$ 33.26万
依托单位：
LEIDEN UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-04 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471834
关键词：
Aerosols Affinity Algorithms Alleles Amino Acids Antigen Presentation Antigen Presentation Pathway Bacille Calmette-Guerin vaccination Binding Bioinformatics Biological CD8-Positive T-Lymphocytes Cell Line Cells Code Consensus Cytomegalovirus Data Data Set Disease Down-Regulation Epitopes Frequencies Future Goals Grant Growth HIV HIV/TB HLA-E antigen Health Human Immune response Immunity Infection Knowledge Lead Ligands Lung infections M. tuberculosis genome Mediating Mission Molecular Morbidity - disease rate Mucosal Immune Responses Mucous Membrane Mus Mycobacterium Infections Mycobacterium tuberculosis Mycobacterium tuberculosis antigens Outcome Pathology Pathway interactions Peptides Peripheral Blood Mononuclear Cell Phagosomes Primates Property Proteome Protocols documentation Qa-1 Antigen Receptor Activation Resistance Rhesus Role SIV Sampling System T cell response T-Cell Receptor T-Lymphocyte T-cell receptor repertoire TCR Activation Tuberculosis Tuberculosis Vaccines United States National Institutes of Health Vaccination Vaccine Design Vaccinee Vaccines Variant Work aerosolized antimicrobial base cellular transduction co-infection comparative cytokine design improved innovation insight macrophage mortality novel novel vaccines pathogen prediction algorithm response vaccination against tuberculosis vaccination strategy vaccine development vaccine strategy

项目摘要

1 Mycobacterium tuberculosis (Mtb) is a remarkably successful pathogen that causes high morbidity and mortality. There 2 is wide consensus that novel vaccines and vaccination strategies are essential to control this rampant disease. One such 3 strategy is inducing T-cell immunity to Mtb antigens that are presented by conserved, non-classical antigen presentation 4 molecules such as human HLA-E, CD1 and MR1. HLA-E is particularly interesting in the context of TB: (1) there are 2 5 coding variants that differ in only one amino acid outside the peptide binding groove; (2) HLA-E is relatively resistant to 6 HIV co-infection mediated downregulation; (3) HLA-E is enriched in Mtb phagosomes, facilitating its loading with Mtb 7 peptides; and (4) in mice, HLA-E (Qa-1b) restricted CD8+ T-cells are associated with protection. We have shown that 8 multiple Mtb epitopes can be presented by HLA-E and are potently recognized by Mtb specific CD8+ T-cells with unique 9 functional properties, including the ability to inhibit intracellular Mtb growth. The long-term goal of our work is to 10 understand the molecular interactions between peptide ligands, HLA-E and T-cell receptor (TCR) molecules in TB, and 11 to harness this knowledge into improved TB vaccination strategies. 12 The objective of our proposal is to define in detail the molecular interactions between HLA-E, peptide and TCR molecules 13 and to characterize HLA-E restricted T-cell responses against these peptides during infection and disease. To this end 14 we will define the exact molecular and structural determinants governing interactions between HLA-E, Mtb peptides 15 and TCR molecules (aim 1). In this aim we will investigate the molecular requirements governing peptide binding to both 16 HLA-E variant molecules and utilize that information to identify novel epitopes in the Mtb genome with improved HLA- 17 E binding and presentation properties. Secondly, available TCR sequences will be employed to generate TCR transduced 18 cell lines to assess critical peptide residues for TCR activation. The expected outcome of this aim is detailed insights in 19 the molecular interactions between HLA-E, peptide and TCR molecules that lead to productive TCR activation. 20 Secondly, we will define the functional and biological significance of Mtb peptide/HLA-E/TCR interactions in non-human 21 primates (NHP) and in human Mtb infection, vaccination and controlled human infection (CHI, with aerosolized BCG) 22 (aim 2). We will construct and use Mtb peptide/HLA-E tetramer pools to determine the frequency and functionality of 23 specific CD8+ T-cells in human samples from BCG vaccinees, latent or active Mtb infection, as well as BAL samples from 24 CHI, in which aerosol-BCG induced mucosal immune responses will be analysed for HLA-E restricted T-cell frequencies 25 and functionalities. To correlate HLA-E restricted T-cells with protective immunity, we will tetramer-profile samples 26 from banked NHP studies that included Mtb challenges with known outcome. The expected outcome of this aim is 27 insights in correlations of HLA-E restricted T-cells with infection, disease and vaccination in humans and NHP. 28 Together these results will impact and significantly deepen our understanding of the role of these non-classical T-cells 29 in Mtb infection, TB disease, vaccination and controlled human BCG infection, and pave the way towards harnessing 30 this knowledge for future TB vaccine design.

1 结核分枝杆菌 (Mtb) 是一种非常成功的病原体，导致高发病率和死亡率。那里 2 广泛共识认为，新型疫苗和疫苗接种策略对于控制这种猖獗的疾病至关重要。这样的一位 3 策略是诱导 T 细胞对通过保守的非经典抗原呈递呈递的 Mtb 抗原产生免疫 4 种分子，如人类 HLA-E、CD1 和 MR1。 HLA-E 在结核病的背景下特别有趣：(1) 有 2 5 种编码变体，仅肽结合沟外的一个氨基酸不同； (2)HLA-E相对抵抗 6 HIV合并感染介导的下调； (3) HLA-E在Mtb吞噬体中富集，有利于其负载Mtb 7种肽； (4) 在小鼠中，HLA-E (Qa-1b) 限制性 CD8+ T 细胞与保护相关。我们已经证明 HLA-E 可以呈递 8 个 Mtb 表位，并且可以被具有独特功能的 Mtb 特异性 CD8+ T 细胞有效识别 9 种功能特性，包括抑制细胞内 Mtb 生长的能力。我们工作的长期目标是 10 了解结核病中肽配体、HLA-E 和 T 细胞受体 (TCR) 分子之间的分子相互作用，以及 11 利用这些知识改进结核病疫苗接种策略。 12 我们提案的目标是详细定义 HLA-E、肽和 TCR 分子之间的分子相互作用 13 并表征感染和疾病期间针对这些肽的 HLA-E 限制性 T 细胞反应。为此 14 我们将定义控制 HLA-E、Mtb 肽之间相互作用的确切分子和结构决定因素 15 和 TCR 分子（目标 1）。为此，我们将研究控制肽与两者结合的分子要求 16 HLA-E 变异分子，并利用该信息来识别 Mtb 基因组中具有改进的 HLA-E 的新表位 17 E 绑定和表示属性。其次，可用的 TCR 序列将用于生成 TCR 转导 18 细胞系评估 TCR 激活的关键肽残基。这一目标的预期结果是详细的见解 19 HLA-E、肽和 TCR 分子之间的分子相互作用导致有效的 TCR 激活。 20 其次，我们将定义 Mtb 肽/HLA-E/TCR 相互作用在非人类中的功能和生物学意义。 21 种灵长类动物 (NHP) 和人类 Mtb 感染、疫苗接种和受控人类感染（CHI，使用雾化卡介苗） 22（目标 2）。我们将构建并使用 Mtb 肽/HLA-E 四聚体池来确定来自 BCG 疫苗接种者、潜伏或活动性 Mtb 感染者的人体样本以及来自 BAL 样本的 23 种特异性 CD8+ T 细胞 24 CHI，其中将分析气溶胶-BCG 诱导的粘膜免疫反应的 HLA-E 限制性 T 细胞频率 25和功能。为了将 HLA-E 限制性 T 细胞与保护性免疫联系起来，我们将对样本进行四聚体分析 26 来自 NHP 库研究，其中包括具有已知结果的 Mtb 挑战。这一目标的预期结果是 27 项有关 HLA-E 限制性 T 细胞与人类和 NHP 感染、疾病和疫苗接种相关性的见解。 28 这些结果将影响并显着加深我们对这些非经典 T 细胞作用的理解 29 在 Mtb 感染、结核病、疫苗接种和受控人类 BCG 感染方面，并为控制铺平道路 30 这些知识有助于未来结核病疫苗的设计。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of donor-unrestricted T-cells, innate lymphoid cells, and NK cells in anti-mycobacterial immunity.

供体非限制性 T 细胞、先天淋巴细胞和 NK 细胞在抗分枝杆菌免疫中的作用。

DOI：
发表时间：
2021
期刊：
影响因子：
8.7
作者：
Ruibal, Paula;Voogd, Linda;Joosten, Simone A;Ottenhoff, Tom H M
通讯作者：
Ottenhoff, Tom H M

Mobilizing unconventional T cells.

动员非常规 T 细胞。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Ottenhoff, Tom H M;Joosten, Simone A
通讯作者：
Joosten, Simone A

Antigen presentation by MHC-E: a putative target for vaccination?

MHC-E 的抗原呈递：疫苗接种的假定目标？

DOI：
发表时间：
2022-05
期刊：
影响因子：
16.8
作者：
Voogd, Linda;Ruibal, Paula;Ottenhoff, Tom H M;Joosten, Simone A
通讯作者：
Joosten, Simone A

Identification of HLA-E Binding Mycobacterium tuberculosis-Derived Epitopes through Improved Prediction Models.

通过改进的预测模型鉴定 HLA-E 结合结核分枝杆菌衍生表位。

DOI：
发表时间：
2022-10-15
期刊：
影响因子：
0
作者：
Ruibal, Paula;Franken, Kees L M C;van Meijgaarden, Krista E;van Wolfswinkel, Marjolein;Derksen, Ian;Scheeren, Ferenc A;Janssen, George M C;van Veelen, Peter A;Sarfas, Charlotte;White, Andrew D;Sharpe, Sally A;Palmieri, Fabrizio;Petrone, Linda
通讯作者：
Petrone, Linda

Mtb HLA-E-tetramer-sorted CD8+ T cells have a diverse TCR repertoire.

Mtb HLA-E-四聚体分选的 CD8 T 细胞具有多样化的 TCR 库。

DOI：
发表时间：
2024-03-15
期刊：
影响因子：
5.8
作者：
Voogd, Linda;Drittij, Anne M H F;Dingenouts, Calinda K E;Franken, Kees L M C;Unen, Vincent van;van Meijgaarden, Krista E;Ruibal, Paula;Hagedoorn, Renate S;Leitner, Judith A;Steinberger, Peter;Heemskerk, Mirjam H M;Davis, Mark M;Scriba, Thomas
通讯作者：
Scriba, Thomas