Pivotal role of VLA-1 in CD8 T cell retention & survival

描述（由申请方提供）：病毒特异性T细胞记忆对于保护宿主免于二次暴露于相同或相关病毒非常重要。这些记忆T细胞的定位及其活化状态决定了二次免疫应答的效率。一个实质性的外淋巴记忆人口，是功能不同的淋巴记忆细胞最近已被描述。这些记忆T细胞可以保留在非淋巴组织中的机制尚不清楚。我们目前的初步数据显示，病毒特异性的CD 8 + T细胞迅速获得整合素VLA-1的表达在流感感染。VLA-1是I型和IV型胶原的受体。VLA-1+流感特异性CD 8 T细胞显示出对细胞凋亡的抗性，并在感染消退期间选择性地在肺和其他非淋巴组织中蓄积。VLA-1+的免疫后抑制减少了肺中流感特异性T细胞的数量，并损害了继发性免疫。由此，我们形成了VLA-1+ CD 8 T细胞与I型和IV型胶原蛋白的结合促进记忆T细胞在非淋巴组织内的保留和存活的假设。这些CD 8 +/VLA - 1+ CD 8 T细胞可能优先保留在非淋巴组织中，以提供针对继发性感染的第一道防线。本提案中的实验将确定VLA-1通过胶原结合在组织中病毒特异性CD 8 T细胞的保留和存活中的作用。我们还将测试VLA-1+记忆T细胞在功能上是不同的并且对于二次免疫保护是重要的预测。

DESCRIPTION (provided by applicant): Virus-specific T cell memory is important to protect the host from secondary exposure to the same or related viruses. The localization of these memory T cells and their activation status determines the efficiency of the secondary immune response. A substantial extralymphoid memory population that is functionally distinct from the lymphoid memory cells has recently been described. The mechanism by which these memory T cells can be retained in non-lymphoid tissue is not known. We present preliminary data that show virus specific CD8+ T cells rapidly acquire expression of the integrin VLA-1 during influenza infection. VLA-1 is the receptor for Type I and IV collagen. VLA-1+ flu-specific CD8 T cells show resistance to apoptosis and selectively accumulate in the lung and other non-lymphoid tissues during resolution of the infection. Postimmune inhibition of VLA-1+ reduces the number of flu-specific T cells in the lung and compromises secondary immunity. From this we have formed the hypothesis that binding of VLA-1+ CD8 T cells to Types I and IV collagen promotes retention and survival of memory T cells within non-lymphoid tissues. These CD8+/VLA - 1+ CD8 T cells may be preferentially retained in non-lymphoid tissues to provide a first line of defense against secondary infection. The experiments in this proposal will establish the role of VLA-1 in the retention and survival of virus-specific CD8 T cells in tissue via collagen-binding. We will also test the prediction that the VLA-1+ memory T cells are functionally distinct and important for secondary immune protection.