CD8+ T cell memory to respiratory virus infections

呼吸道病毒感染是全世界发病率和死亡率的主要原因，迫切需要改进目前针对这些病原体的疫苗。CD8+细胞毒性T淋巴细胞(CTL)在控制一次呼吸道病毒感染中起核心作用，是抗二次感染的异型免疫的基础。然而，对于CD8+T细胞对粘膜表面(如肺)感染的诱导、持续和召回反应，以及与异型免疫的关系，人们知之甚少。在目前的提案中，将使用两种成熟的呼吸道病毒感染小鼠模型(仙台病毒和流感病毒)来研究抗原特异性CD8+T细胞反应的召回。初步数据显示，在呼吸道病毒感染后，大量抗原特异性T细胞不仅存在于脾和局部引流淋巴结中，而且存在于肺组织和呼吸道中。有趣的是，肺中的记忆CD8+T细胞在表型、相对频率和寿命方面与在脾中观察到的细胞不同。识别不同的记忆CD8+T细胞群体提出了一些关于记忆细胞亚群对回忆反应的相对贡献的问题。和一般的保护性异型免疫。因此，这项提案的总体目标是了解CD8+记忆T细胞对呼吸道感染的诱导、分布和召回，以期改进疫苗设计。目的1进一步鉴定肺中抗原特异性的CD8+记忆T细胞，以确定其表型和功能特征，(Ii)其在体内的基础增殖率，以及(Iii)影响其在肺中维持的因素。对肺中抗原特异性T细胞记忆细胞的性质的详细信息对于了解一般的异型免疫是重要的。目的2将研究不同的记忆细胞群与肺部感染的回忆反应之间的关系。这些研究将集中在明确定义的抗原特异性记忆细胞亚群上，这些细胞持续存在于肺或脾中。目的3研究不同疫苗策略诱导的记忆CD8+T细胞的分布和表型，以及它们在召回反应中的相对有效性。重点将放在诱导肺粘膜免疫的策略上。综上所述，这些研究将产生关于记忆T细胞群体和粘膜表面保护性异型免疫之间关系的详细信息。彻底了解肺部对感染的细胞免疫反应对于未来的疫苗开发是至关重要的。

Respiratory virus infections are a major cause of morbidity and mortality worldwide and there is an urgent need to improve current vaccines against these pathogens. CD8+ cytotoxic T lymphocytes (CTL) play a central role in controlling primary respiratory virus infection and are the foundation of heterotypic immunity against secondary infections. However, relatively little is known about the induction, persistence, and recall of CD8+ T cell responses to infections at mucosal surfaces, such as the lung, and the relationship to heterotypic immunity.. In the current proposal, two well-established murine models of respiratory virus infections (Sendai virus and influenza virus) will be used to investigate the recall of antigen-specific CD8+ T cell responses. The preliminary data shown that substantial numbers of antigen-specific T cells persist not only in the spleen and local draining lymph nodes, but also in the lung tissue and airways following respiratory virus infection. Interestingly, memory CD8+ T cells in the lungs differ from those observed in the spleen in terms of phenotype, relative frequency, and longevity. The identification of distinct populations of memory CD8+ T cells raises a number of questions regarding the relative contributions of memory cell subsets to recall responses. And protective heterotypic immunity in general. Thus, the overall goal of this proposal is to understand the induction, distribution, and recall of CD8+ memory T cells to respiratory infections with a view to improving vaccine design. Aim 1 will further characterize antigen-specific CD8+ memory T cell sin the lungs to determine (i) their phenotypic and functional characteristics, (ii) their basal proliferation rates in vivo, and (iii) the factors that impact their maintenance in the lung. Detailed information on the nature of Antigen- specific T cells memory cells in the lung is important for understanding heterotypic immunity in general. Aim 2 will investigate the relationship between distinct populations of memory cells and the recall responses to infection in the lung. The studies will focus on clearly defined sub- populations of antigen-specific memory cells that persist in either the lungs or the spleen. Aim 3 will investigate the distribution and phenotypes of memory CD8+ T cells elicited by different vaccine strategies, and their relative efficacy in a recall response. Particular emphasis will be placed on strategies that induce mucosal immunity in the lung. Taken together, these studies will generate detailed information on the relationship between memory T cell populations and protective heterotypic immunity at a mucosal surface. A thorough understanding of the cellular immune response to infection in the lung is essential for future vaccine development.