清華祁海組發現GPR174-CCL21模塊影響體液免疫應答的兩性差異
作者：
小柯機器人發布時間：2019/12/26 14:41:52
清華大學祁海團隊發現GPR174-CCL21模塊影響體液免疫應答的兩性差異。相關論文於2019年12月25日在線發表在《自然》雜誌上。
研究人員表明，在雄性和雌性小鼠中產生生發中心的B細胞之間存在內在差異。研究人員發現，抗原激活的雄性B細胞不能像雌性B細胞那樣有效地將自己定位在次生淋巴器官的濾泡中心（這是生發中心發育的地方）。此外，GPR174是一種X染色體編碼的G蛋白偶聯受體，可抑制雄性小鼠（而非雌性小鼠）生發中心的形成。這種效應是B細胞所固有的，並且與GPR174增強的B細胞朝向濾泡的T細胞-B細胞邊界的位置相關，此外與雄性而非雌性B細胞從S1PR2驅動的濾泡中心定位中分散開來有關。
以GPR174依賴性方式誘導B細胞遷移的條件培養基的生化分離可確定CCL21為GPR174配體。響應CCL21，GPR174觸發鈣流並優先誘導雄性B細胞遷移。與雌性B細胞相比，雄性中GPR174還與更多的Gαi蛋白相關。摘除睪丸的小鼠的雄性B細胞表現出受損的GPR174介導的向CCL21的遷移，而睪丸激素治療可以挽救這一缺陷。睪丸激素處理過小鼠的雌性B細胞表現出類似雄性的GPR174–Gαi締合和GPR174介導的遷移。從雄性B細胞中刪除GPR174導致更有效地定位於濾泡中心，形成更多的生發中心，並增加了對B細胞依賴性實驗性自身免疫性腦脊髓炎的敏感性。
通過鑑定GPR174作為CCL21的受體，並證明了其對B細胞定位和參與生發中心的性別依賴性控制，研究人員揭示了一種機制，即通過該機制來微調B細胞生理，以賦予體液免疫性別二態性。
據悉，男性對免疫和感染的體液免疫反應以及對抗體介導的自身免疫的敏感性較低。但是，這種性別二態性的潛在機制尚未得到很好的理解。
附：英文原文
Title: A GPR174–CCL21 module imparts sexual dimorphism to humoral immunity
Author: Ruozhu Zhao, Xin Chen, Weiwei Ma, Jinyu Zhang, Jie Guo, Xiu Zhong, Jiacheng Yao, Jiahui Sun, Julian Rubinfien, Xuyu Zhou, Jianbin Wang, Hai Qi
Issue&Volume: 2019-12-25
Abstract: Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males1,2,3. However, the mechanisms underlying such sexual dimorphism are not well understood. Here we show that there are intrinsic differences between the B cells that produce germinal centres in male and female mice. We find that antigen-activated male B cells do not position themselves as efficiently as female B cells in the centre of follicles in secondary lymphoid organs, in which germinal centres normally develop. Moreover, GPR174—an X-chromosome-encoded G-protein-coupled receptor—suppresses the formation of germinal centres in male, but not female, mice. This effect is intrinsic to B cells, and correlates with the GPR174-enhanced positioning of B cells towards the T-cell–B-cell border of follicles, and the distraction of male, but not female, B cells from S1PR2-driven follicle-centre localization. Biochemical fractionation of conditioned media that induce B-cell migration in a GPR174-dependent manner identifies CCL21 as a GPR174 ligand. In response to CCL21, GPR174 triggers a calcium flux and preferentially induces the migration of male B cells; GPR174 also becomes associated with more Gαi protein in male than in female B cells. Male B cells from orchidectomized mice exhibit impaired GPR174-mediated migration to CCL21, and testosterone treatment rescues this defect. Female B cells from testosterone-treated mice exhibit male-like GPR174–Gαi association and GPR174-mediated migration. Deleting GPR174 from male B cells causes more efficient positioning towards the follicular centre, the formation of more germinal centres and an increased susceptibility to B-cell-dependent experimental autoimmune encephalomyelitis. By identifying GPR174 as a receptor for CCL21 and demonstrating its sex-dependent control of B-cell positioning and participation in germinal centres, we have revealed a mechanism by which B-cell physiology is fine-tuned to impart sexual dimorphism to humoral immunity.
DOI: 10.1038/s41586-019-1873-0
Source: https://www.nature.com/articles/s41586-019-1873-0