TSLP通过促进MoDCs成熟分化和维持CLRs表达诱导过敏性Th2型免疫反应的分子机制研究

It remains unclear the basic mechanism of allergy that how are allergens upstaken and presented by antigen presenting cells (APC), and then induce allergic Th2 type immune response.It is found in our preliminary study that TSLP promote immature MoDCs maturation and maintain high-expression of C type lectin receptors (CLRs) Dectin-2,CD206, and CD209, and TSLP-MoDCs maight upatke and present allergen OVA thourgh CLRs,and then contributes to induce allergic Th2 type immune responses through MoDCs maturation and IL-33 secretion. Therefore, we suggest this hypothesis that TSLP promotes MoDCs maturation and maintaining CLRs expression, which contributes to TSLP-MoDCs uptake and present allergens via CLRs and then induce allergic Th2 type immune responses through synergetic effects of CLRs pathways activated by allergens and co-stimulatory pathways, for example, synergetic effects of IL-33 and OX40L. We shall further clarify in our next study that:1.the molecuar mechanism that how TSLP promote immature MoDCs maturation and maintain CLRs expression. 2. the molecuar mechanism that how TSLP treated MoDCs induce allergic Th2 type immune responses through synergetic effects of CLRs pathways activated by allergens and co-stimulatory pathways.

“过敏原如何被抗原提呈细胞（APC）摄取提呈并进一步诱导过敏性Th2型免疫反应”这一过敏发生的基本机制尚不清楚. 我们的前期研究发现胸腺基质淋巴细胞生成素(TSLP)促进未成熟MoDCs成熟分化并维持C型凝集素受体（CLRs）-Dectin-2，CD206，CD209高表达，TSLP-MoDCs可通过CLRs摄取提呈过敏原OVA，促进MoDC分泌IL-33及诱导Th2免疫反应。为此，我们提出“TSLP促进MoDCs成熟分化与CLRs表达，TSLP-MoDCs通过CLRs摄取提呈过敏原激活相关信号通路并分泌IL-33等炎症因子，与共刺激分子（OX40L等）协同作用诱导过敏性Th2免疫反应的发生”的假说。本项目将进一步研究阐明TSLP如何促进MoDCs成熟分化及CLRs表达，及过敏原激活CLRs途径与共刺激分子共同作用诱导Th2免疫反应的具体分子机制。

“过敏原如何被抗原提呈细胞（APC）摄取提呈并进一步诱导过敏性Th2型免疫反应”这一过敏发生的基本机制尚不清楚. 我们的前期研究发现胸腺基质淋巴细胞生成素(TSLP)促进未成熟MoDCs成熟分化并维持C型凝集素受体（CLRs）-Dectin-2，CD206，CD209高表达，TSLP-MoDC s可通过CLRs摄取提呈过敏原OVA，促进MoDC分泌IL-33及诱导Th2免疫反应。为此，我们提出“ TSLP促进MoDCs成熟分化与CLRs表达，TSLP-MoDCs通过CLRs摄取提呈过敏原激活相关信号通路并分泌IL-33等炎症因子，与共刺激分子（OX40L等）协同作用诱导过敏性Th2免疫反应的发生”的假说。本研究发现前炎症细胞因子TSLP 促进人CD14+单核细胞FcRγ及相关受体FcεR1、Dectin-2、CD16 表达增加，也发现与正常对照相比，AD患者CD14+单核细胞Dectin-2异常过表达；进一步研究证实TSLP促进单核细胞FCER1G调控序列DNA低甲基化，用免疫共沉淀与CHIP-PCR技术证实其DNA去甲基化机制是通过激活pSTAT5 募集DNA去甲基化酶TET2 结合至FCER1G 启动子序列上，导致FCER1G调控序列DNA去甲基化；同时本研究发现TSLP促进DCs诱导Th2过敏反应新机制，TSLP诱导MoDCs是一种特殊的DCs（TSLP-DCs），既是成熟分化的DCs又维持Dectin-2等识别受体高表达，使其兼有未成熟DCs过敏原摄取提呈功能又有成熟DCs诱导Th分化的功能，进一步研究体外试验证实TSLP-DCs通过Dectin-2诱导OVA特异性Th2/Th17免疫反应。