Division of Immune Receptors and T Cell Activation, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
Front Immunol. 2022 Aug 23;13:956694. doi: 10.3389/fimmu.2022.956694. eCollection 2022.
The engagement of the herpesvirus entry mediator (HVEM, TNFRSF14) by the B and T lymphocyte attenuator (BTLA) represents a unique interaction between an activating receptor of the TNFR-superfamily and an inhibitory receptor of the Ig-superfamily. BTLA and HVEM have both been implicated in the regulation of human T cell responses, but their role is complex and incompletely understood. Here, we have used T cell reporter systems to dissect the complex interplay of HVEM with BTLA and its additional ligands LIGHT and CD160. Co-expression with LIGHT or CD160, but not with BTLA, induced strong constitutive signaling HVEM. In line with earlier reports, we observed that interaction of BTLA and HVEM prevented HVEM co-stimulation by ligands on surrounding cells. Intriguingly, our data indicate that BTLA mediated inhibition is not impaired in this heterodimeric complex, suggesting a dominant role of BTLA co-inhibition. Stimulation of primary human T cells in presence of HVEM ligands indicated a weak costimulatory capacity of HVEM potentially owed to its engagement by BTLA. Furthermore, experiments with T cell reporter cells and primary T cells demonstrate that HVEM antibodies can augment T cell responses by concomitantly acting as checkpoint inhibitors and co-stimulation agonists.
疱疹病毒进入介体（HVEM，TNFRSF14）与 B 和 T 淋巴细胞衰减器（BTLA）的结合代表了 TNFR 超家族的激活受体和 Ig 超家族的抑制受体之间的独特相互作用。BTLA 和 HVEM 都被认为参与了人类 T 细胞反应的调节，但它们的作用是复杂的，尚未完全理解。在这里，我们使用 T 细胞报告系统来剖析 HVEM 与 BTLA 及其额外配体 LIGHT 和 CD160 之间的复杂相互作用。与 LIGHT 或 CD160 共表达，但与 BTLA 共表达，诱导 HVEM 的强烈组成型信号传导。与早期报道一致，我们观察到 BTLA 和 HVEM 的相互作用阻止了 HVEM 配体在周围细胞上的共刺激。有趣的是，我们的数据表明 BTLA 介导的抑制在这种异二聚体复合物中不受损害，这表明 BTLA 共抑制的主导作用。在 HVEM 配体存在的情况下刺激原代人 T 细胞表明 HVEM 具有较弱的共刺激能力，这可能归因于其与 BTLA 的结合。此外，使用 T 细胞报告细胞和原代 T 细胞的实验表明，HVEM 抗体可以通过同时作为检查点抑制剂和共刺激激动剂来增强 T 细胞反应。
