Epitope-specific T cell activation to complement TB immunity and vaccine efficacy

描述（由申请人提供）：结核病（TB）是疫苗开发的一个特别具有挑战性的目标，至少部分原因是结核分枝杆菌具有非常有效的机制，可以逃避抗原特异性效应T细胞的消除。我们最近发现结核分枝杆菌用于限制抗原特异性CD4效应细胞抗细菌功效的一种机制是限制肺部感染部位抗原的可用性：当CD4效应细胞识别的抗原数量不足时，效应T细胞被激活的频率不足以消除细菌。我们还发现，我们可以通过给药一种特定的免疫显性表位肽来克服结核病中抗原的有限可用性，这种抗原可以增加对该表位特异性的CD4效应T细胞的局部激活，并减少肺部的细菌负担。在这个项目中，我们将使用来自结核分枝杆菌的特异性表位肽的管理来增强自然发生的和疫苗诱导的T细胞反应，以绕过抗原（表位）缺陷。这将揭示限制性抗原可用性作为一种阻碍结核病免疫的机制的定量贡献，并将使我们能够表征限制效应T细胞在结核病中的功效的其他机制。我们将首先优化表位肽给药的剂量和间隔，以优化CD4效应T细胞的抗细菌活性，并将确定表位肽的组合是否提供更大的抗细菌活性而没有毒性。随后，我们将研究可能限制表位肽给药抗细菌功效的特定宿主机制，以确定这些机制在限制T细胞应答在结核病中的功效方面的重要性。此外，我们将结合表位肽与暴露前接种和暴露后接种最先进的蛋白质亚基结核疫苗，以确定暴露前接种是否增强表位肽接种的抗结核作用，并确定表位肽接种是否增强结核暴露后接种的抗结核作用。在进一步的实验中，我们将继续我们最近的观察，即给药CD4 T细胞特异性表位肽会导致结核分枝杆菌感染小鼠肺部CD8 T细胞的CD4 T细胞依赖性激活。在这种情况下，我们将确定CD4 T细胞与CD8 T细胞交流的机制，并确定这些机制在多大程度上有助于结核病中CD4 T细胞的抗细菌活性。拟议的研究包括与结核病疫苗开发领域的一家国际领先企业的合作研究，这些研究将利用新的方法和概念，深入了解限制自然产生和疫苗诱导的结核病免疫效力的机制。此外，它们将通过绕过和调节目前限制结核病疫苗效力的免疫逃避的特定机制，为开发结核病免疫治疗的新方法提供基础。

DESCRIPTION (provided by applicant): Tuberculosis (TB) is an especially challenging target for vaccine development, at least in part because Mycobacterium tuberculosis possesses highly effective mechanisms for evading elimination by antigen-specific effector T cells. We recently discovered that one mechanism used by M. tuberculosis to limit the antimycobacterial efficacy of antigen-specific CD4 effector cells is to limit the availability of antigen at the site of infecion in the lungs: when antigens recognized by CD4 effector cells are not available in sufficient quantity, effector T cells are not activated with the frequency needed to eliminate the bacteria. We also discovered that we can overcome the limited availability of antigen in TB by administration of a specific immunodominant epitope peptide, which increases local activation of CD4 effector T cells specific for that epitope, and reduces the bacterial burden in the lungs. In this project, we will use administration of specific epitope peptides from M. tuberculosis to enhance naturally-occurring and vaccine-induced T cell responses in order to bypass antigen (epitope) deficiency. This will reveal the quantitative contribution of limiting antigen availabiliy as a mechanism that impedes TB immunity, and will allow us to characterize other mechanisms that restrict the efficacy of effector T cells in TB. We will first optimize the dosage and interva for epitope peptide administration that optimizes the antimycobacterial activity of CD4 effector T cells, and will determine whether combinations of epitope peptides provide greater antimycobacterial activity without toxicity. We will subsequently examine specific host mechanisms that may limit the antimycobacterial efficacy of epitope peptide administration, to determine the significance of these mechanisms in limiting the efficacy of T cell responses in TB. In addition, we will combine epitope peptide administration with pre-exposure and post-exposure vaccination with state-of- the-art protein subunit TB vaccines, to determine whether pre-exposure vaccination enhances the antimycobacterial effects of epitope peptide administration, and to determine whether epitope peptide administration enhances the antimycobacterial effects of post-exposure vaccination in TB. In additional experiments, we will follow up on our recent observation that administration of a CD4 T cell-specific epitope peptide causes CD4 T cell-dependent activation of CD8 T cells in the lungs of M. tuberculosis-infected mice. We will identify the mechanisms used by CD4 T cells to communicate with CD8 T cells in this context, and we will determine the extent to which those mechanisms contribute to the antimycobacterial activity of CD4 T cells in TB. The proposed studies, which include collaborative studies with an international leader in TB vaccine development, will utilize novel approaches and concepts to provide insight into the mechanisms that limit the efficacy of naturally-occurring and vaccine-induced immunity in TB. In addition, they will provide a basis for development of novel approaches to immunotherapy in TB, by bypassing and modulating specific mechanisms of immune evasion that currently limit the efficacy of TB vaccines.