Lymphatic endothelial cell capture and maintenance of antigen

 说明(申请人提供)：基于使用活的、减毒的传染病病原体的疫苗接种(即痘苗病毒，MMR)可以产生持续数十年的免疫记忆，而不需要任何增强。这些减毒活疫苗既能产生体液免疫记忆，又能产生细胞免疫记忆，这是保护性免疫记忆持续时间延长的主要原因。此外，有充分的证据表明，来自感染源的抗原在感染从宿主清除后会持续很长一段时间。这种抗原的持久性被证明有助于维持不同功能的抗原特异性记忆细胞池，这些记忆细胞在清除感染挑战方面表现出不同的效率。虽然除FDCs外的基质细胞参与了持久性抗原的捕获和维持，但这些细胞的身份、它们在次级细胞中的位置 淋巴组织，以及决定抗原如何在这些细胞中/在这些细胞上持续存在的潜在机制，从来没有得到明确的证明。我们已经发表了大量关于疫苗佐剂的性质及其诱导强大细胞免疫的能力的文章。我们现在可以证明，这种基于亚单位的疫苗方法，类似于病毒挑战，导致抗原在宿主中长期存在。令人惊讶的是，我们发现持久的抗原不在 FDC和/或成纤维细胞网状细胞(FRC)网络，而不是捕获并保持在LEC上或之内。LEC增殖和抗原捕获的结合确定了一种以前未被认识的机制，通过该机制，次级淋巴组织中的间质保持对已启动强烈反应的抗原，有效地将这些抗原在正常免疫反应高峰期之后持续很长一段时间。我们的结果是唯一一份确定LECs在抗原捕获和存档中的核心作用的报告。有了这些数据 考虑到问题，我们假设晶状体上皮细胞的增殖响应于局部炎症条件和T细胞的扩张诱导其表达抗原捕获所需的分子。我们进一步假设，特定的DC亚群可以从淋巴结的包膜下区域获得这种LEC存档的抗原，并将该抗原呈递给循环中的抗原特异性记忆T细胞，从而增加记忆T细胞向组织的募集，增加T细胞的自我更新，增强T细胞效应器功能，或以上各项的某种组合。这些假说最终预测，持久性抗原的消除将对记忆T细胞对感染攻击的反应速度和/或幅度产生负面影响。由于我们的初步数据显示T细胞、DC和LECs在疫苗接种或病毒攻击后的抗原捕获和存档过程中扮演着关键角色，因此我们将针对每种细胞类型在这一过程中的作用来测试我们所陈述的假设。

 DESCRIPTION (provided by applicant): Vaccinations that are based on the use of live, attenuated infectious agents (ie. Vaccinia virus, MMR) can produce immune memory lasting for many decades without any need for boosting. These live attenuated vaccinations generate both humoral and cellular immune memory, accounting for much of the increased duration of protective immune memory. In addition, it is well documented that antigen derived from infectious agents persists for an extended period of time after the infection is cleared from the host. This persistence of antigen has been shown to help maintain different functional pools of antigen specific memory cells which display varying efficiencies in the clearance of an infectious challenge. While stromal cells other than FDCs have been implicated in the capture and maintenance of persisting antigen, the identity of these cells, their location within the secondary lymphoid tissue, and the underlying mechanisms determining how antigen persists in/on these cells, have never been clearly demonstrated. We have published extensively on the nature of vaccine adjuvants and their capacity to elicit robust cellular immunity. We can now show that this subunit-based vaccine approach, similar to viral challenge, results in long term persistence of antigen in the host. Surprisingly, we found that the persisting antigen is maintained not within the FDC and/or the fibroblastic reticular cell (FRC) network, but rather captured and held on or within the LECs. The coupling of LEC proliferation and antigen capture identifies a previously unappreciated mechanism by which the stroma in secondary lymphoid tissue maintains antigens against which a robust response has been initiated, in effect "archiving" these antigens for periods of time lasting well after the peak of normal immune response. Our results are the only report to identify the central role of LECs in antigen capture and archiving. With these data and questions in mind, we hypothesize that proliferation of LECs in response to cues derived from local inflammatory conditions and T cell expansion induces their expression of molecules necessary for antigen capture. We further hypothesize that specific subsets of DCs can acquire this LEC-archived antigen from within the subcapsular region of the lymph node and present the antigen to circulating antigen specific memory T cells, thereby increasing memory T cell recruitment to the tissue, increasing T cell self-renewal, enhancing T cell effector function, or some combination of all of the above. These hypotheses ultimately predict that the elimination of persisting antigen will negatively affect the speed and/or magnitude of the memory T cell response to infectious challenge. Because our preliminary data show critical roles for T cells, DCs, and LECs in the process of antigen capture and archiving after vaccination or viral challenge, we will test our stated hypotheses with specific aims focusing on the role of each cell type in this process.