Regulation of Langerhans Cell Migration by Invariant Gamma Delta T Cells

描述(申请人提供)：皮炎是狼疮的一种常见表现，可导致疤痕和毁容。狼疮性皮炎通常很难治疗，对其发病机制知之甚少。皮肤的外层，即表皮，包含两种免疫细胞，朗格汉斯细胞(LC)和树突状表皮T细胞(DETC)。皮肤的相对简单使其成为研究器官水平免疫耐受的理想模型。最近的研究指出朗格汉斯细胞是皮肤耐受性的重要调节细胞。我们的实验室最近发现，易患狼疮性皮炎的小鼠LC迁移受损。众所周知，DETCs有助于促进伤口愈合，但其整体功能尚不清楚。来自我们实验室的令人兴奋的新数据表明，DETCs具有一种未知的功能，即它们调节LC的迁移。用α-半乳糖神经酰胺(GalCer)治疗可改善皮炎，增加表皮中DETC的数量，并恢复狼疮易感小鼠的LC迁移。在这项授权中，我们假设DETCs调节LC的迁移，而LC-DETC在皮肤中的相互作用起到保护皮肤免受炎症的调节网络的作用。为了验证这一假说，我们将：确定DETC在LC迁移中的作用，并研究DETCs调控LC迁移的机制(目标1)。在目标2中，我们将调查在MRL小鼠中发现的LC迁移缺陷的相关因素。根据我们的初步发现，MRL-LPR小鼠体内DETC数量也显著减少，DETC-LC似乎在体内和体外相互作用，我们假设狼疮小鼠LC迁移受损是由于皮肤中DETC数量减少；增加DETC数量将促进LC迁移，并减少皮肤炎症。未来的研究将开始将我们对DETCs和LC迁移的研究过渡到人类样本。更好地了解控制LC迁移的因素可能会导致控制狼疮性皮炎的新疗法。

DESCRIPTION (provided by applicant): Dermatitis is a common manifestation of lupus that can cause scarring and disfigurement. Lupus dermatitis is often difficult to treat and relatively little is known about its pathogenesis. The outer layer of the skin, the epidermis, contains two immune cells, the Langerhans cell (LC) and dendritic epidermal T cells (DETC). The relative simplicity of the skin makes it an ideal model for studying organ level immune tolerance. Recent studies have pointed to Langerhans cells as important regulators of skin tolerance. Our lab has recently shown that LC migration is impaired in mice prone to lupus dermatitis. DETCs are known to help promote wound healing but their overall function remains unclear. Exciting new data from our lab have shown a hereto- unknown function for the DETCs, that they regulate LC migration. Treatment with alpha-galactosylceramide (GalCer) improves dermatitis, increases DETC numbers in the epidermis, and restores LC migration in lupus prone mice. In this grant, we hypothesize that DETCs regulate the migration of LCs, and that LC-DETC interaction in the skin serves as a regulatory network that protects against skin inflammation. To test this hypothesis, we will: determine the role of DETC in LC migration, and investigate the mechanism or mechanisms by which DETCs regulate LC migration (Aim 1). In Aim 2, we will investigate the factors responsible for the LC migration defect seen in MRL mice. Guided by our preliminary findings that MRL-lpr mice also have a marked reduction in DETC numbers and that DETC-LC appear to interact with each other in vivo and in vitro, we hypothesize that impaired LC migration in lupus mice is due to reduced numbers of DETC in skin; increasing DETC numbers will enhance LC migration, and reduce skin inflammation. Future studies will start to transition our studies of DETCs and LC migration to human samples. Better understanding of the factors regulating LC migration may lead to novel therapies for the control of lupus dermatitis.