Viral infections are controlled, and very often cleared, by activated T lymphocytes. The inducible co-stimulator (ICOS) mediates its functions by binding to its ligand ICOSL, enhancing T-cell activation and optimal germinal center (GC) formation. Here, we show that ICOSL is heavily downmodulated during infection of antigen presenting cells by different herpesviruses. We found that, in murine cytomegalovirus (MCMV), the immunoevasin m138/fcr-1 physically interacts with ICOSL, impeding its maturation and promoting its lysosomal degradation. This viral protein counteracts T-cell responses, in an ICOS-dependent manner, and limits virus control during the acute MCMV infection. Additionally, we report that blockade of ICOSL in MCMV-infected mice critically regulates the production of MCMV-specific antibodies due to a reduction of T follicular helper and GC B cells. Altogether, these findings reveal a novel mechanism evolved by MCMV to counteract adaptive immune surveillance, and demonstrates a role of the ICOS:ICOSL axis in the host defense against herpesviruses.

中文翻译：

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巨细胞病毒限制抗原呈递细胞上 ICOSL 的表达，从而使 T 细胞共刺激失效并导致免疫逃避

病毒感染由活化的 T 淋巴细胞控制，并且经常被清除。诱导型共刺激物 (ICOS) 通过与其配体 ICOSL 结合来介导其功能，增强 T 细胞活化和最佳生发中心 (GC) 形成。在这里，我们表明 ICOSL 在不同疱疹病毒感染抗原呈递细胞期间被严重下调。我们发现，在小鼠巨细胞病毒 (MCMV) 中，immunevasin m138/fcr-1 与 ICOSL 发生物理相互作用，阻碍其成熟并促进其溶酶体降解。这种病毒蛋白以 ICOS 依赖性方式抵消 T 细胞反应，并限制急性 MCMV 感染期间的病毒控制。此外，我们报告说，由于 T 滤泡辅助细胞和 GC B 细胞的减少，在 MCMV 感染的小鼠中阻断 ICOSL 会严重调节 MCMV 特异性抗体的产生。总之，这些发现揭示了 MCMV 进化出的一种新机制来抵消适应性免疫监视，并证明了 ICOS:ICOSL 轴在宿主防御疱疹病毒中的作用。