环氧化酶COX-1通过Tfh调控GC-B细胞的机制研究

The cyclooxygenase (COX) enzymes and their metabolites are known as important modulators of humoral immune response. In our previous study, COX-1-derived TxA2 has been demonstrated to regulate early B cell differentiation (Blood, 2014), and our recent studies indicated that COX-1 played an essential role in germinal B cell (GC-B) formation. The experimental evidence includes: transfer of follicular helper T cells (Tfh) could rescue the impaired GC-B percentage in COX-1 KO mice to the level of wild type (WT) control; in the model of KLH immunization, we found decreased level of GC-B cells in the spleen and dLN of COX-1 KO mice, with reduced Tfh cells; the mRNA expression of COX-1 was higher in sorted Tfh compared with non-Tfh cells. Based on above observations, we propose that COX-1 may promote GC-B formation through the regulation of Tfh development. To test this hypothesis, we plan to study in the folloing aspects: confirm the role of COX-1 in regulating GC-B development is mediated by Tfh cells; study the role of COX-1 in Tfh development and function during the influenza virus infection; explore the molecular mechanisms of COX-1 in regulating Tfh cells; demonstrate the pathological significance in clinical samples. This research will uncover the important molecular mechanism of COX-1-mediated GC-B formation in humoral immune response, and will also provide potential therapeutic target for auto-immune diseases.

环氧化酶COX及其代谢产物在体液免疫应答发挥重要作用。前期我们报道了COX-1调控早期B细胞发育的机制(Blood,2014)。新近我们研究结果表明：COX-1可调控生发中心B细胞（GC-B）的形成，且过继转移滤泡辅助性T细胞（Tfh）可回复COX-1-KO小鼠中GC-B水平。利用KLH进行免疫,发现与WT相比，KO小鼠脾脏中GC-B比例显著下降，伴随Tfh减少；基因表达结果表明COX-1在Tfh中表达显著高于non-Tfh。据此我们提出：COX-1可通过调控Tfh来促进GC-B形成。为验证此假说，我们拟从以下方面进行研究：确证Tfh介导COX-1对GC-B的调控；利用流感模型研究COX-1对Tfh发育及功能的调控；研究COX-1调控Tfh的分子机制；最后利用临床样品研究其病理意义。以上研究将揭示COX-1调控B细胞活化及体液免疫应答的重要分子机制，为自身免疫性疾病提供免疫干预靶标。

环氧化酶COX及其代谢产物在体液免疫应答发挥重要作用，在前期COX-1调控早期 B细胞发育的机制(Blood,2014)的工作基础上，发现COX-1可调控生发中心B细胞（GC-B ）的形成，且过继转移滤泡辅助性T细胞（Tfh）可回复COX-1-KO小鼠中GC-B水平。在我们的研究中，首先利用基因表达证实COX-1在Tfh中表达显著高于non-Tfh，接下来利用流感模型、KLH免疫模型确证了COX-1对Tfh发育及功能的调控，并发现这一调控是cell-intrinsic。最后研究下游分子机制，证实这一调控作用依赖于COX-1的下游产物PGE2，说明COX-1通过EP2/EP4受体结合PGE2来调节Tfh细胞的发育及功能。该项目的顺利实施将为自身免疫性疾病提供免疫干预靶标。