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靶标，至少部分是因为结核分枝杆菌具有逃避抗原特异性效应T细胞消除的高效机制。我们最近发现M.在结核病中，限制抗原特异性CD4效应细胞的抗分枝杆菌功效的目的是限制抗原在肺中感染部位的可用性：当CD4效应细胞识别的抗原不能以足够的量获得时，效应T细胞不能以消除细菌所需的频率活化。我们还发现，我们可以通过施用特异性免疫显性表位肽来克服TB中抗原的有限可用性，这增加了对该表位特异性的CD4效应T细胞的局部活化，并减少了肺中的细菌负荷。在本项目中，我们将使用来自M的特异性表位肽的施用。结核病的免疫应答，以增强天然存在的和疫苗诱导的T细胞应答，从而绕过抗原（表位）缺陷。这将揭示限制抗原可用性作为阻碍TB免疫的机制的定量贡献，并且将允许我们表征限制效应T细胞在TB中的功效的其他机制。我们将首先优化优化CD4效应T细胞的抗分枝杆菌活性的表位肽施用的剂量和间隔，并将确定表位肽的组合是否提供更大的抗分枝杆菌活性而没有毒性。我们随后将检查可能限制表位肽施用的抗分枝杆菌功效的特定宿主机制，以确定这些机制在限制TB中T细胞应答的功效中的意义。此外，我们将联合收割机表位肽给药与暴露前和暴露后接种最先进的蛋白亚基TB疫苗相结合，以确定暴露前接种是否增强表位肽给药的抗分枝杆菌作用，并确定表位肽给药是否增强TB中暴露后接种的抗分枝杆菌作用。在另外的实验中，我们将继续我们最近的观察，即给予CD4 T细胞特异性表位肽导致M.感染结核病的小鼠。我们将确定在这种情况下，CD4 T细胞与CD8 T细胞沟通的机制，并确定这些机制在多大程度上有助于TB中CD4 T细胞的抗分枝杆菌活性。拟议的研究包括与结核病疫苗开发国际领导者的合作研究，将利用新的方法和概念来深入了解限制结核病天然存在和疫苗诱导免疫效力的机制。此外，它们将为开发结核病免疫治疗的新方法提供基础，通过绕过和调节目前限制结核病疫苗功效的免疫逃避的特定机制。

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.