CD100-Plexin-B2介导“T细胞抵抗”参与口腔扁平苔藓发病的机制研究

In the chronic progress of oral lichen planus (OLP), the imbalance between the activation of T effective cells and its suppression by regulatory T cells (Tregs) is a critical aspect that causes "T cell resistance" and consequent persistent CD8+ T-cell proliferation and activation, but the underling mechanism has not been elucidated. CD100 is a newly-recognized immune regulator functioning in a ligand-receptor manner, which plays important roles in T-cell modulation, but its implication in OLP has not been fully understood. In our preliminary study, we found that the level of CD100 in serum of OLP patients was significantly upregulated. Parallelly, its high-affinity receptor Plexin-B2 was specifically expressed on cell surface of patient-derived CD8+ T cells in circulation. In vitro, CD100 effectively prevented CD8+ T cells from apoptosis under the incubation of TGF-β, a representative suppressive mediator of Treg, accompanied with the activation of Rho GTPase family members RhoA and Rac1. Thus, we hypothesize that by modulating CD8+ T effective cells, CD100-Plexin-B2-Rho GTPase cascade causes "T cell resistance" and contributes to OLP progression. To test this hypothesis, in this project, we will use cellular and molecular immunologic techniques and establish allograft mice model to demonstrate that the effect of CD100 on CD8+ T-cell functions causes CD8+ T-cell resistance to Treg suppression and leads to OLP progression. We also aim to identify the functional receptor of CD100 on CD8+ T effective cells and their downstream signaling pathway, thus together expecting to provide new insight into the mechanism of CD100-mediated T-cell dysregulation in OLP pathogenesis.

在口腔扁平苔藓（OLP）慢性迁延的病理过程中，调节性T细胞（Treg）对效应T细胞负向调控的失衡是导致“T细胞抵抗”和随后CD8+T细胞持续增殖、活化的关键因素，然其机制不明。前期研究中我们发现：在OLP外周血中，新型免疫调节分子CD100水平显著增高，其高亲和力受体Plexin-B2特异性表达于CD8+T细胞表面；且CD100可在体外有效降低Treg负向调控介质TGF-β作用下CD8+T细胞的凋亡率并活化Rho GTPase家族分子，由此推测CD100-Plexin-B2-Rho GTPase信号轴通过介导“T细胞抵抗”参与OLP的发病和慢性迁延。本项目拟应用细胞和分子免疫学技术及构建异体移植动物模型，证明CD100通过调节CD8+T细胞功能介导其抵抗Treg负向调控参与OLP的发病，并阐明这一作用的受体信号和分子机制，以期全面揭示CD100介导的T细胞免疫紊乱在OLP发病机制中的作用。

口腔扁平苔藓（Oral lichen planus, OLP）是常见的口腔黏膜慢性炎症性疾病，其病程迁 延、极易复发，临床上缺 乏治疗 OLP 的有效手段。研究表明T 细胞免疫紊乱是 OLP 发病机制的中心环节，CD100/Semaphorin 4D 是重要的免疫调节分子，参与调控 T、B 细胞免疫应答。我们前期的研究表明效应 CD8+T 细胞对 Treg 细胞所介导的负向免疫调节的抵抗是 OLP慢性迁延的关键因素，然其具体机制尚不清楚。本项目从临床样本、细胞水平、动物模型三方面，观察CD100和Plexin-B2的表达及相互作用调控TGF-β作用下OLP患者CD8+T细胞生物学功能和介导“T细胞抵抗”的现象，明确CD100-Plexin-B2通过活化Rho GTPase介导CD8+T细胞抵抗Treg细胞负向免疫调控的机制；并进一步筛选和验证CD100-Plexin-B2活化的Rho GTPase家族信号分子，最终确定CD100-Plexin-B2-Rho GTPase信号通路介导“T细胞抵抗”在OLP发病中的作用。结果将有助于深入认识CD100及其受体调控效应T细胞功能在OLP发病中的作用，阐明OLP发病中CD8+T细胞持续增殖、活化和病程慢性迁延的关键机制，为系统认识OLP的临床现象及明确其防治策略提供新的思路。