CD40-signalling abrogates induction of RORγt(+) Treg cells by intestinal CD103(+) DCs and causes fatal colitis.
CD40-signalling abrogates induction of RORγt(+) Treg cells by intestinal CD103(+) DCs and causes fatal colitis.
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DOI：
10.1038/ncomms14715
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发表时间：
2017-03-09
影响因子：
16.6
通讯作者：
Brocker T
中科院分区：
文献类型：
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作者：
Barthels C;Ogrinc A;Steyer V;Meier S;Simon F;Wimmer M;Blutke A;Straub T;Zimber-Strobl U;Lutgens E;Marconi P;Ohnmacht C;Garzetti D;Stecher B;Brocker T
肠组织中的免疫稳态依赖于调节性T（Treg）细胞的产生。CD 103+树突状细胞（DC）从肠腔获取微生物来源的物质，转运至引流淋巴结，并产生受体相关孤儿γt+（RORγt+）Helios−诱导的Treg（iTreg）细胞。在这里，我们显示CD 40信号作为一个微生物独立的信号，可以诱导迁移的CD 103 + DC从固有层（LP）的肠系膜淋巴结。具有组成性CD 11 c特异性CD 40信号传导的转基因小鼠LP中CD 103 + DC数量减少，RORγt+Helios− iTreg细胞频率降低，炎症性Th 1/Th 17反应加剧，微生物群特异性免疫球蛋白滴度高，生态失调和致命性结肠炎，但在其他组织中未检测到病理学。我们的数据表明，CD 40依赖性机制能够消除DC诱导的iTreg细胞，并表明CD 40 L/CD 40信号传导轴可能能够干预新的iTreg细胞的产生，以反调节免疫抑制，以增强免疫力。CD 103+树突状细胞诱导iTreg细胞维持肠道中的免疫平衡，但CD 40-信号传导如何调节这一过程尚不清楚。在这里，作者表明具有组成性CD 11 c特异性CD 40信号传导的小鼠改变了CD 103+树突状细胞迁移，减少了iTreg细胞诱导和致命性结肠炎。
Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103+ dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt+ (RORγt+) Helios−-induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103+ DCs from the lamina propria (LP) to the mesenteric lymph nodes. Transgenic mice with constitutive CD11c-specific CD40-signalling have reduced numbers of CD103+ DCs in LP and a low frequency of RORγt+Helios− iTreg cells, exacerbated inflammatory Th1/Th17 responses, high titres of microbiota-specific immunoglobulins, dysbiosis and fatal colitis, but no pathology is detected in other tissues. Our data demonstrate a CD40-dependent mechanism capable of abrogating iTreg cell induction by DCs, and suggest that the CD40L/CD40-signalling axis might be able to intervene in the generation of new iTreg cells in order to counter-regulate immune suppression to enhance immunity. CD103+ dendritic cells induce iTreg cells to maintain immune balance in the gut, but how CD40-signalling regulates this process is unclear. Here the authors show that mice with constitutive CD11c-specific CD40-signalling have altered CD103+ dendritic cell migration, reduced iTreg cell induction, and fatal colitis.