Ocular herpes simplex virus 1 (HSV-1) infection leads to an immunopathogenic disease called herpes stromal keratitis (HSK), in which CD4⁺ T cell-driven inflammation contributes to irreversible damage to the cornea. Herpesvirus entry mediator (HVEM) is an immune modulator that activates stimulatory and inhibitory cosignals by interacting with its binding partners, LIGHT (TNFSF14), BTLA (B and T lymphocyte attenuator), and CD160. We have previously shown that HVEM exacerbates HSK pathogenesis, but the involvement of its binding partners and its connection to the pathogenic T cell response have not been elucidated. In this study, we investigated the role of HVEM and its binding partners in mediating the T cell response using a murine model of ocular HSV-1 infection. By infecting mice lacking the binding partners, we demonstrated that multiple HVEM binding partners were required for HSK pathogenesis. Surprisingly, while LIGHT^−/−, BTLA^−/−, and CD160^−/− mice did not show differences in disease compared to wild-type mice, BTLA^−/− LIGHT^−/− and CD160^−/− LIGHT^−/− double knockout mice showed attenuated disease characterized by decreased clinical symptoms, increased retention of corneal sensitivity, and decreased infiltrating leukocytes in the cornea. We determined that the attenuation of disease in HVEM^−/−, BTLA^−/− LIGHT^−/−, and CD160^−/− LIGHT^−/− mice correlated with a decrease in gamma interferon (IFN-γ)-producing CD4⁺ T cells. Together, these results suggest that HVEM cosignaling through multiple binding partners induces a pathogenic Th1 response to promote HSK. This report provides new insight into the mechanism of HVEM in HSK pathogenesis and highlights the complexity of HVEM signaling in modulating the immune response following ocular HSV-1 infection.

中文翻译：

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疱疹病毒进入介质结合伙伴介导眼部单纯疱疹病毒 1 感染的免疫发病机制。


眼部单纯疱疹病毒 1 (HSV-1) 感染会导致一种称为疱疹基质角膜炎 (HSK) 的免疫致病性疾病，其中 CD4 ⁺ T 细胞驱动的炎症会导致角膜不可逆损伤。疱疹病毒进入介质 (HVEM) 是一种免疫调节剂，通过与其结合伙伴 LIGHT (TNFSF14)、BTLA（B 和 T 淋巴细胞衰减剂）和 CD160 相互作用来激活刺激和抑制共信号。我们之前已经表明，HVEM 加剧了 HSK 发病机制，但其结合伙伴的参与及其与致病性 T 细胞反应的联系尚未阐明。在这项研究中，我们使用眼部 HSV-1 感染的小鼠模型研究了 HVEM 及其结合伴侣在介导 T 细胞反应中的作用。通过感染缺乏结合伴侣的小鼠，我们证明 HSK 发病机制需要多个 HVEM 结合伴侣。令人惊讶的是，虽然 LIGHT ^−/− 、BTLA ^−/−和 CD160 ^−/−小鼠与野生型小鼠相比没有表现出疾病差异，但 BTLA ^−/− LIGHT ^−/−和 CD160 ^−/− LIGHT ^−/−小鼠的病情却加倍基因敲除小鼠表现出疾病减轻，其特征是临床症状减少、角膜敏感性保留增加以及角膜中浸润白细胞减少。我们确定 HVEM ^−/− 、BTLA ^−/− LIGHT ^−/−和 CD160 ^−/− LIGHT ^−/−小鼠的疾病减弱与产生γ干扰素 (IFN-γ) 的 CD4 ⁺ T 细胞的减少相关。 总之，这些结果表明 HVEM 通过多个结合伙伴的协同信号传导诱导致病性 Th1 反应以促进 HSK。该报告提供了对 HVEM 在 HSK 发病机制中的新见解，并强调了 HVEM 信号在调节眼部 HSV-1 感染后免疫反应中的复杂性。