SUMMARY

Leukocyte function-associated antigen 1 (LFA-1) is the most widely expressed member of the β2 integrin family of cell-cell adhesion molecules. Although LFA-1 is thought to regulate multiple aspects of T cell immunity, its role in the response of CD8⁺ T cells to viral infections remains unclear. Indeed, compelling clinical evidence shows that loss of LFA-1 function predisposes to infection in humans but animal models show limited to no susceptibility to infection. Here, we addressed this conundrum in a mouse model of infection with lymphocytic choriomeningitis virus (LCMV), where CD8⁺ T cells are necessary and sufficient to confer protection. To this end, we followed the fate and function of wild-type and LFA-1 deficient virus-specific CD8⁺ T cells and assessed the effect of blocking anti-LFA-1 monoclonal antibody in the outcome of infection. Our analysis of viral clearance and T cell responses using transcriptome profiling reveals a role for LFA-1 as a gatekeeper of effector T cell survival and dysfunction that when defective can predispose to LCMV infection.

概括

白细胞功能相关抗原 1 (LFA-1) 是细胞-细胞粘附分子 β2 整合素家族中表达最广泛的成员。尽管 LFA-1 被认为调节 T 细胞免疫的多个方面，但其在 CD8 ⁺ T 细胞对病毒感染的反应中的作用仍不清楚。事实上，令人信服的临床证据表明，LFA-1 功能的丧失会导致人类感染，但动物模型显示对感染的敏感性有限。在这里，我们在淋巴细胞性脉络丛脑膜炎病毒 (LCMV) 感染的小鼠模型中解决了这个难题，其中 CD8 ⁺ T 细胞是必要的并且足以提供保护。为此，我们追踪了野生型和 LFA-1 缺陷型病毒特异性 CD8 ⁺T 细胞并评估阻断抗 LFA-1 单克隆抗体对感染结果的影响。我们使用转录组分析对病毒清除和 T 细胞反应的分析揭示了 LFA-1 作为效应 T 细胞存活和功能障碍的看门人的作用，当有缺陷时，它会导致 LCMV 感染。