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

描述(由申请人提供)：病毒特异性T细胞记忆对于保护宿主免受相同或相关病毒的二次暴露非常重要。这些记忆T细胞的定位和激活状态决定了二次免疫反应的效率。最近已经描述了一种在功能上不同于淋巴存储细胞的实质上的淋巴外记忆群体。这些记忆T细胞保留在非淋巴组织中的机制尚不清楚。我们提供的初步数据显示，在流感感染期间，病毒特异性CD8+T细胞迅速获得整合素VLA-1的表达。VLA-1是I型和IV型胶原的受体。VLA-1+Flu特异性CD8 T细胞表现出抗凋亡能力，并在感染消退期间选择性地聚集在肺和其他非淋巴组织中。免疫后抑制VLA-1+会减少肺中流感特异性T细胞的数量，并损害二次免疫。由此，我们形成了一个假设，即VLA-1+CD8 T细胞与I型和IV型胶原结合可促进记忆T细胞在非淋巴组织中的保留和存活。这些CD8+/VLA-1+CD8 T细胞可能优先保留在非淋巴组织中，以提供抵御二次感染的第一道防线。该方案中的实验将确定VLA-1通过胶原结合在组织中保留和存活病毒特异性CD8T细胞的作用。我们还将测试VLA-1+记忆T细胞在功能上是独特的，对二级免疫保护很重要的预测。

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.