VISTA regulates type I interferon response to ultraviolet light

项目摘要 对紫外线的敏感性影响约80%的狼疮患者，并可加重局部皮肤病， 导致全身性疾病发作。使狼疮患者易患 光敏性和驱动对UV光的炎症反应的机制很差， 明白我们发现，单次暴露于紫外线会导致快速的I型干扰素（IFN-γ）， I）在人和鼠皮肤中的体内应答。紫外线是干扰素I的强有力的刺激物 反应是特别相关的，因为狼疮患者（约75%）在两个组织中具有高IFN-I特征， 皮肤组织和外周血细胞，表明病情加重。因此，有一个关键的 需要发现是什么调节了IFN-I在紫外线和狼疮皮肤中的产生。 最近的研究表明，缺乏VISTA会导致狼疮样皮肤病，并加速 狼疮小鼠模型中的全身性疾病。观察到的病理学伴随着 这表明VISTA可以调节IFN-I应答。我确 在一些实施方案中，证明了激动性抗VISTA抗体抑制人IFN-1应答。 单核细胞虽然发现狼疮患者细胞的转录谱类似于 小鼠VISTA-/-细胞的表达提示VISTA在狼疮发病机制中的重要作用， VISTA调节狼疮皮肤中的IFN-I反应，并且对UV光的反应是未知的。在这里， 我们假设VISTA负调节IFN-1对紫外线的反应， 在角质形成细胞中的活性调节基线和UV触发的IFN-I产生。测试这些 假设，我们将追求以下具体目标：在目标1中，我们将定义VISTA如何 在体内调节局部和全身IFN-I对UV光的应答。我们预测IFN-1反应 在VISTA-/-小鼠的皮肤和血液中的UV光的强度和/或持续时间将更大， 与VISTA充分对照相比。我们将研究靶向治疗的潜力 使用激动性抗人VISTA调节IFN-1对UV光的应答 在人源化VISTA基因敲入小鼠中使用单克隆抗体。在目标2中，我们将描述紫外光 通过角质形成细胞触发IFN-I产生并定义角质形成细胞VISTA功能。蜂窝 暴露于紫外线的皮肤中IFN-I的来源和类别未知，VISTA的功能也未知 由角质形成细胞表达。考虑到紫外线照射后皮肤中IFN-b的快速产生，我们 将研究角质形成细胞作为IFN-γ可能来源的贡献， 正常和狼疮小鼠品系的皮肤。我们还将定义角质形成细胞特异性VISTA 在VISTA条件性敲除小鼠和原代狼疮角质形成细胞中的体内功能。

Project Summary Sensitivity to UV light affects ~80% of lupus patients and can exacerbate local skin disease and lead to systemic disease flares. The molecular pathways predisposing lupus patients to photosensitivity and the mechanisms driving the inflammatory responses to UV light are poorly understood. We showed that a single exposure to UV light leads to a rapid type I interferon (IFN- I) response in human and murine skin in vivo. That UV light is a potent stimulus of the IFN-I response is particularly relevant as lupus patients (~75%) have a high IFN-I signature in both the skin tissue and the peripheral blood cells, indicative of worse disease. Therefore, there is a critical need to discover what regulates the IFN-I production in response to UV light and in lupus skin. Recent studies showed that deficiency in VISTA result in lupus-like skin disease and accelerate systemic disease in lupus mouse models. The observed pathologies were accompanied by an increase in the IFN-I signature, suggesting VISTA can modulate the IFN-I response. Indeed, we demonstrated that an agonistic anti-VISTA antibody inhibits the IFN-I response in human monocytes. While findings that the transcriptional profile of cells from lupus patients resembles that of murine VISTA-/- cells suggest an important role for VISTA in lupus pathogenesis, how VISTA modulates the IFN-I response in lupus skin and in response to UV light is unknown. Here, we hypothesize that VISTA negatively regulates the IFN-I response to UV light and that VISTA activity in keratinocytes modulates the baseline and UV-triggered IFN-I production. To test these hypotheses, we will pursue the following specific aims: In Aim 1, we will define how VISTA regulates local and systemic IFN-I response to UV light in vivo. We predict that the IFN-I response to UV light in the skin and blood of VISTA-/- mice will be of greater magnitude and/or duration, compared to VISTA-sufficient controls. We will examine the therapeutic potential of targeting VISTA to modulate the IFN-I response to UV light using an agonistic anti-human VISTA monoclonal antibody in humanized VISTA knock-in mice. In Aim 2, we will characterize UV-light triggered IFN-I production by keratinocytes and define keratinocyte VISTA function. The cellular source and class of IFN-I in UV light exposed skin is unknown as is the function of VISTA expressed by keratinocytes. Given the rapid IFN-b production in the skin after UV exposure, we will investigate the contribution of keratinocytes as the likely source of IFN-Is in UV light-exposed skin of normal and lupus mouse strains. We will also define the keratinocyte-specific VISTA function in vivo in VISTA conditional knockout mice and in primary lupus keratinocytes.