Determinants of T Cell Immunity to Tuberculosis Vaccines

有效的宿主免疫结核分枝杆菌是依赖于T细胞介导的反应，对特定抗原的芽孢杆菌。虽然每年有200多万人死于结核病，但大约90%对结核菌产生正常免疫反应的感染者从未发生临床疾病。这证明了有效的免疫应答在限制或预防由M引起的疾病中的重要性。结核病，并提供了一个合理的发展，有效的疫苗，以预防疾病。近年来研究表明，M.结核病的病原体是脂质，其可对调节宿主的免疫应答具有深远影响。两个参与脂质生物合成的基因位点在M.结核病、pcaA和 panCD与小鼠中杆菌的毒力降低和清除增强有关。第三个基因位点RD 1在M.结核病很可能是通过控制有毒蛋白质的分泌。我们假设M.携带这些基因的功能性缺失的结核病将在受感染的动物中产生增强的T细胞应答和更强的保护性免疫。此外，我们提出，T细胞对M。通过使用α-半乳糖基神经酰胺家族中激活CD 1限制性NK T细胞的新型合成糖脂佐剂，可以进一步增强结核病相关蛋白抗原。提出了以下三个具体目标：（1）评估 pcaA、panCD和RD 1缺失对T细胞对MHC I类和II类呈递表位的反应的影响; 2）分析M. 3）确定α-半乳糖基神经酰胺家族中的合成免疫调节脂质对减毒M.结核病疫苗株。该项目将通过与该项目其他成员的广泛合作网络以及使用其所有核心设施来实现。结合这些方法来增强免疫原性可能会导致高效减毒活M的发展。结核病疫苗。这将是一个重要工具，可加强目前为减轻全球人口负担所作的不充分努力。 结核病和预防多重耐药菌株的出现。

Effective host immunity to Mycobacterium tuberculosis is dependent on T cell-mediated responses against specific antigens of the bacillus. Although more than 2 million people die from tuberculosis every year, approximately 90% of infected humans who mount a normal immune response to the bacterium never develop clinical disease. This demonstrates the importance of a potent immune response in limiting or Preventing disease caused by M. tuberculosis, and provides a rationale for the development of an effective vaccine to prevent disease. Recently, it has become clear that many virulence-promoting factors produced by M. tuberculosis are lipids, which can have profound effects on modulating the immune response of the host. Functional inactivation of two genetic loci involved in lipid biosynthesis in M. tuberculosis, pcaA and panCD, are associated with reduced virulence and enhanced clearance of the bacilli in mice. A third genetic locus called RD1 plays a major role in virulence of M. tuberculosis most likely by controlling the secretion of toxic proteins. We hypothesize that M. tuberculosis harboring functional deletions of these genes will generate enhanced T cell responses and more robust protective immunity in infected animals. In addition, we propose that the T cell response against M. tuberculosis-associated protein antigens can be further enhanced by using novel synthetic glycolipid adjuvants in the alpha-galacotosyl ceramide family that activate CD1-restricted NK T cells. The following three specific aims are proposed: 1) To assess the impact of deletion of pcaA, panCD and RD1 on T cell responses to MHC class I and class II presented epitopes; 2) To analyze the basis for adaptive immunity to attenuated vaccine strains of M. tuberculosis in CD4-deficient mice; and 3) to determine the effect of synthetic immunomodulatory lipids in the alpha-galactosyl ceramide family on the T cell response and protective immunity induced by attenuated M. tuberculosis vaccine strains. This project will be enabled through an extensive network of collaborations with other members of this program project and the use of all of its core facilities. Combining these approaches for enhancing immunogenicity may lead to the development of highly effective attenuated live M. tuberculosis vaccines. This would be a major tool for enhancing the currently inadequate efforts to reduce the global burden of tuberculosis and prevent the emergence of multidrug resistant strains.