Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.
Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.
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DOI：
10.1084/jem.20131397
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发表时间：
2014-08-25
期刊：
影响因子：
--
通讯作者：
Steinman RM
中科院分区：
文献类型：
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作者：
Anandasabapathy N;Feder R;Mollah S;Tse SW;Longhi MP;Mehandru S;Matos I;Cheong C;Ruane D;Brane L;Teixeira A;Dobrin J;Mizenina O;Park CG;Meredith M;Clausen BE;Nussenzweig MC;Steinman RM
对蛋白质疫苗的保护性免疫由Flt 3L依赖的经典LN驻留树突状细胞控制，并由迁移性树突状细胞抑制。DC对于启动免疫至关重要。目前疫苗生物学的范例是从外周组织迁移的DC和经典的淋巴驻留DC（cDC）在引流LN中合作以启动T细胞的引发和增殖。在这里，我们观察到皮下免疫是Fms样酪氨酸激酶3配体（Flt 3L）依赖性的。Flt 3L在免疫后迅速分泌; Flt 3缺失使T细胞应答降低50%。Flt 3L增强整体T细胞和体液免疫以及迁移DC（migDC）和LN驻留cDC的数量和抗原捕获能力。然而，令人惊讶的是，我们发现免疫由cDC控制，并在体内由migDC主动调节。Langerin+ DC的缺失或DC迁移的阻断提高免疫力。与免疫调节作用一致，转录组学分析揭示了小鼠和人类中不同的皮肤migDC亚群聚集在一起，并共享免疫抑制基因表达和调节途径。这些数据表明，对蛋白疫苗的保护性免疫由Flt 3L依赖性LN驻留cDC控制。
Protective immunity to protein vaccines is controlled by Flt3L-dependent classical LN-resident dendritic cells, and dampened by migratory dendritic cells. DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin+ DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.
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