NKp46+CD3+ T-Cells As A Novel Target For Vaccines Against bovine TB

NKp46 CD3 T 细胞作为牛结核病疫苗的新靶点

• 批准号: BB/N004647/1
• 负责人: Ivan Morrison
• 金额: $ 61.71万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN004647%2F1
• 关键词: NKp46+CD3+; Cells; Novel; Target; Vaccines

Bovine tuberculosis (bTB) is the most important disease affecting the UK cattle industry. Failure of the current 'test-and-slaughter' policy to constrain the spread of bTB has led to a review of what strategies should be implemented in future to improve the control of this disease. BCG, the only licensed bTB vaccine, exhibits variable and unpredictable levels of protection and is not DIVA compliant so can't be used in current disease control programmes. Consequently, there is a need to develop vaccines that confer more reliable immunity and can be integrated with bTB field surveillance. Development of such vaccines requires a better understanding of i) the components of the immune response that contribute to protective immunity and ii) how immune responses can be exploited to discriminate between vaccinated and Mb-infected animals. Although it is well established that protective immunity against TB is cell mediated, the precise protective immunological mechanisms are still undefined. Evidence indicates that conventional peptide-MHCII restricted CD4+ T cell responses are critical for immunity and that for optimal anti-TB immunity peptide-MHCI restricted CD8+ T-cells are also required. In humans a large proportion of the cellular anti-TB response if composed of non-conventional lipid-specific CD1-restricted T-cells; the range of anti-mycobacterial effector functions exhibited by these cells indicates that they also contribute to host defence against TB. Consequently, it has been proposed that lipids may constitute novel antigens that could be used to enhance the immunogenicity and efficacy of next-generation TB vaccines. Lipids are attractive vaccine candidates as they i) activate both innate-like and adaptive T-cell responses, ii) can have adjuvant properties and iii) are presented by non-polymorphic CD1 genes and therefore (unlike MHC-restricted peptides) have utility across an outbred population. In addition, some lipids don't induce responses against PPD, so could be used as DIVA reagents. Although cattle lipid-specific T-cell responses have been reported in bTB, knowledge of their role in anti-bTB immunity is negligible. Recent studies conducted by our laboratories have identified a novel population of non-conventional NKp46+CD3+ bovine T-cells and demonstrated that a subset of these cells respond to PIM, a group of lipids from M. bovis in a proportion of Mb-infected animals. In this project we propose to gain information on lipid-specific T-cell responses in bTB by analysing NKp46+CD3+ T-cells during a BCG-immunisation/Mb-challenge study. We will also perform studies to identify the range of antigenic TB lipids and determine which are immunogenic and so could contribute to new effective bTB vaccines. The objectives of the project are to:1. Quantify and track the NKp46+CD3+ T-cell responses following BCG vaccination and subsequent exposure to M. bovis. This will help determine if NKp46+CD3+ T-cells are functioning as innate and/or adaptive effector T-cells and if BCG immunisation forms a memory population recalled during Mb challenge.2. Examine the function of NKp46+CD3+ T-cells recognising mycobacteria. This will define the role of NKp46+CD3+ T-cells in anti-TB immunity. Data from objectives 1 and 2 will also be used to examine if NKp46+CD3+ T-cell responses correlate with anti-bTB protection conferred by BCG immunisation.3. Identify additional mycobacterial lipids that could be used to generate NKp46+CD3+ (and other) bovine T-cell responses. It is likely that multiple TB lipids will be antigenic in cattle and that some lipid-specific T-cells may lie out-with the NKp46+CD3+ T-cell subset. This study will expand the knowledge of the bTB lipid antigen repertoire (and also determine if any could be exploited for DIVA applications).4. Identify which mycobacterial lipids elicit NKp46+CD3+ T-cell responses in vivo. This will establish which lipids are immunogenic in vivo and are therefore genuine vaccine candidates.

牛结核病（bTB）是影响英国养牛业的最重要的疾病。目前限制结核传播的“试验和屠宰”政策的失败导致了对未来应该实施哪些战略以改善对这种疾病的控制的审查。卡介苗是唯一获得许可的bTB疫苗，具有可变和不可预测的保护水平，并且不符合DIVA，因此不能用于当前的疾病控制规划。因此，有必要开发能够提供更可靠的免疫力并可与结核分枝杆菌现场监测相结合的疫苗。开发这类疫苗需要更好地了解：(1)促进保护性免疫的免疫反应组成部分和(2)如何利用免疫反应来区分接种疫苗的动物和mb感染的动物。虽然已经确定对结核病的保护性免疫是细胞介导的，但确切的保护性免疫机制仍然不清楚。有证据表明，传统的多肽- mhci限制性CD4+ T细胞反应对免疫至关重要，而为了获得最佳的抗结核免疫，多肽- mhci限制性CD8+ T细胞也是必需的。在人类中，很大一部分细胞抗结核反应是由非常规的脂质特异性cd1限制性t细胞组成的；这些细胞表现出的抗分枝杆菌效应功能范围表明，它们也有助于宿主防御结核病。因此，有人提出脂质可能构成新的抗原，可用于增强下一代结核病疫苗的免疫原性和效力。脂质是有吸引力的疫苗候选物，因为它们i)激活先天样t细胞反应和适应性t细胞反应，ii)可以具有佐剂特性，iii)由非多态性CD1基因呈现，因此（与mhc限制性肽不同）在近亲繁殖群体中具有效用。此外，一些脂类对PPD没有诱导反应，因此可以用作DIVA试剂。尽管牛脂质特异性t细胞反应在bTB中有报道，但它们在抗bTB免疫中的作用的知识可以忽略不计。我们实验室最近进行的研究发现了一种新型的非传统NKp46+CD3+牛t细胞群，并证明这些细胞的一个亚群对PIM（一组来自牛支原体的脂质）有反应。在这个项目中，我们建议通过在bcg免疫/ mb攻击研究中分析NKp46+CD3+ t细胞来获得bTB中脂质特异性t细胞应答的信息。我们还将开展研究，以确定抗原性结核脂质的范围，并确定哪些具有免疫原性，从而有助于开发新的有效结核疫苗。该项目的目标是：1。量化和跟踪卡介苗接种和随后暴露于牛分枝杆菌后的NKp46+CD3+ t细胞反应。这将有助于确定NKp46+CD3+ t细胞是否作为先天和/或适应性效应t细胞起作用，以及卡介苗免疫是否在Mb挑战期间形成记忆群体。检测NKp46+CD3+ t细胞识别分枝杆菌的功能。这将确定NKp46+CD3+ t细胞在抗结核免疫中的作用。目的1和目的2的数据也将用于检查NKp46+CD3+ t细胞反应是否与卡介苗免疫所赋予的抗btb保护相关。鉴定可用于产生NKp46+CD3+（和其他）牛t细胞反应的分枝杆菌脂质。牛的多种结核脂质可能具有抗原性，一些脂质特异性t细胞可能存在于NKp46+CD3+ t细胞亚群中。这项研究将扩大对bTB脂质抗原库的认识（并确定是否有任何抗原可以用于DIVA应用）。鉴定哪些分枝杆菌脂质在体内引起NKp46+CD3+ t细胞反应。这将确定哪些脂质在体内具有免疫原性，因此是真正的疫苗候选物。

项目成果

Identification and Phenotype of MAIT Cells in Cattle and Their Response to Bacterial Infections.

• DOI: 10.3389/fimmu.2021.627173
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Edmans MD;Connelley TK;Jayaraman S;Vrettou C;Vordermeier M;Mak JYW;Liu L;Fairlie DP;Maze EA;Chrun T;Klenerman P;Eckle SBG;Tchilian E;Benedictus L
• 通讯作者: Benedictus L

Hydrophobic Mycobacterial Antigens Elicit Polyfunctional T Cells in Mycobacterium bovis Immunized Cattle: Association With Protection Against Challenge?

• DOI: 10.3389/fimmu.2020.588180
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Benedictus L;Steinbach S;Holder T;Bakker D;Vrettou C;Morrison WI;Vordermeier M;Connelley T
• 通讯作者: Connelley T