A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity
A GPR174-CCL21 module imparts sexual dimorphism to humoral immunity
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DOI：
10.1038/s41586-019-1873-0
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发表时间：
2019-12-25
期刊：
影响因子：
64.8
通讯作者：
Qi, Hai
中科院分区：
文献类型：
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作者：
Zhao, Ruozhu;Chen, Xin;Qi, Hai
男性和女性B细胞对生发中心的定位和贡献能力不同，这取决于G蛋白偶联的导向受体GPR174及其趋化因子配体CCL21。男性对免疫和感染的体液免疫反应和对抗体介导的自身免疫的易感性通常较低(1-3)。然而，这种性二型性的机制还没有被很好地理解。在这里，我们表明，在雄性和雌性小鼠中产生生发中心的B细胞之间存在内在的差异。我们发现，抗原激活的男性B细胞并不像女性B细胞那样有效地将自己定位在次级淋巴器官的滤泡中心，而次级淋巴器官通常在那里发育生发中心。此外，GPR174-一种X染色体编码的G蛋白偶联受体-抑制雄性小鼠生发中心的形成，而不是雌性小鼠。这种作用是B细胞固有的，并与GPR174增强的B细胞向毛囊T细胞-B细胞边界的定位以及男性B细胞(而不是女性B细胞)从S1PR2驱动的毛囊中心定位的分散相关。对以GPR174依赖的方式诱导B细胞迁移的条件培养液进行生化分级，确定CCL21为GPR174配体。作为对CCL21的响应，GPR174触发钙离子流并优先诱导男性B细胞的迁移；GPR174还与男性B细胞中比女性B细胞中更多的GαI蛋白相关。来自去睾丸小鼠的雄性B细胞表现出GPR174介导的向CCL21迁移的受损，而睾酮治疗可以修复这一缺陷。来自睾酮处理小鼠的雌性B细胞表现出类似男性的GPR174-GαI关联和GPR174介导的迁移。从男性B细胞中删除GPR174会导致更有效地定位到毛囊中心，形成更多的生发中心，并增加对B细胞依赖的实验性自身免疫性脑脊髓炎的易感性。通过确认GPR174是CCL21的受体，并展示了它对B细胞定位和参与生发中心的性别依赖性控制，我们揭示了B细胞生理学被微调以赋予体液免疫性别二型性的机制。
Male and female B cells show differing abilities to localize and contribute to germinal centres, in a way that depends on the G-protein-coupled guidance receptor GPR174 and its chemokine ligand CCL21.Humoral immune responses to immunization and infection and susceptibilities to antibody-mediated autoimmunity are generally lower in males(1-3). 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 G alpha i 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-G alpha i 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.