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很重要。这些记忆T细胞的定位及其激活状态决定了二次免疫反应的效率。大量淋巴外记忆细胞在功能上不同于淋巴记忆细胞。这些记忆T细胞在非淋巴组织中保留的机制尚不清楚。我们提供的初步数据显示，病毒特异性CD8+ T细胞在流感感染期间迅速获得整合素VLA-1的表达。VLA-1是I型和IV型胶原蛋白的受体。在感染消退期间，vra -1+流感特异性CD8 T细胞表现出对凋亡的抵抗力，并选择性地在肺和其他非淋巴组织中积累。免疫后抑制vra -1+可减少肺部流感特异性T细胞的数量，损害继发免疫。由此，我们形成了一种假设，即VLA-1+ CD8 T细胞与I型和IV型胶原结合可促进记忆T细胞在非淋巴组织内的保留和存活。这些CD8+/VLA - 1+ CD8 T细胞可能优先保留在非淋巴组织中，为抵抗继发性感染提供第一道防线。本实验将通过胶原结合来确定vas -1在组织中病毒特异性CD8 T细胞的保留和存活中的作用。我们还将测试预测，即vra -1+记忆T细胞在功能上是独特的，对二次免疫保护很重要。

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.