Migratory CD11b(+) conventional dendritic cells induce T follicular helper cell-dependent antibody responses.
Migratory CD11b(+) conventional dendritic cells induce T follicular helper cell-dependent antibody responses.
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DOI：
10.1126/sciimmunol.aam9169
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发表时间：
2017-12-01
影响因子：
24.8
通讯作者：
Eisenbarth SC
中科院分区：
文献类型：
--
作者：
Krishnaswamy JK;Gowthaman U;Zhang B;Mattsson J;Szeponik L;Liu D;Wu R;White T;Calabro S;Xu L;Collet MA;Yurieva M;Alsén S;Fogelstrand P;Walter A;Heath WR;Mueller SN;Yrlid U;Williams A;Eisenbarth SC
滤泡辅助性T细胞（Tfh）是CD 4 + T细胞的一个亚群，在接种疫苗期间促进抗体产生。传统的树突状细胞（cDC）有效地引发Tfh细胞;然而，关于哪种cDC指导Tfh细胞分化的结论在最近的研究之间存在差异。我们发现，这些差异可能存在，因为在小鼠模型中用于免疫的不寻常的位点，其差异偏倚DC亚群接触抗原。我们使用鼻内免疫作为将抗原递送至所有组织DC亚群的生理相关暴露途径。使用单个DC亚群功能受损的小鼠和不同抗原制剂的组合，我们确定了CD 11b+迁移性2型cDC（cDC 2）对于Tfh诱导是必要且足够的。鸟嘌呤核苷酸交换因子DOCK 8的DC特异性缺失导致CD 11b + cDC 2迁移至肺引流淋巴结的孤立性丢失，但不导致CD 103 + cDC 1迁移至肺引流淋巴结。在DC特异性Dock 8或Irf 4敲除小鼠中，cDC 2迁移或发育受损分别导致Tfh细胞引发减少，而Batf 3 −/−小鼠中CD 103 + cDC 1的丢失则没有。cDC 2依赖性Tfh细胞引发的损失损害了抗体介导的对活流感病毒攻击的保护。我们发现，迁移cDC 2独特的携带抗原进入亚解剖区域的淋巴结Tfh细胞引发发生的T-B边界。这项工作确定了负责Tfh细胞依赖性抗体应答的DC亚群，特别是当抗原剂量有限或在粘膜部位遇到时，这可能最终为疫苗的配制和递送提供信息。
T follicular helper (Tfh) cells are a subset of CD4+ T cells that promote antibody production during vaccination. Conventional dendritic cells (cDCs) efficiently prime Tfh cells; however, conclusions regarding which cDC instructs Tfh cell differentiation have differed between recent studies. We found that these discrepancies might exist because of the unusual sites used for immunization in murine models, which differentially bias which DC subsets access antigen. We used intranasal immunization as a physiologically relevant route of exposure that delivers antigen to all tissue DC subsets. Using a combination of mice in which the function of individual DC subsets is impaired and different antigen formulations, we determined that CD11b+ migratory type 2 cDCs (cDC2s) are necessary and sufficient for Tfh induction. DC-specific deletion of the guanine nucleotide exchange factor DOCK8 resulted in an isolated loss of CD11b+ cDC2, but not CD103+ cDC1, migration to lung-draining lymph nodes. Impaired cDC2 migration or development in DC-specific Dock8 or Irf4 knockout mice, respectively, led to reduced Tfh cell priming, whereas loss of CD103+ cDC1s in Batf3−/− mice did not. Loss of cDC2-dependent Tfh cell priming impaired antibody-mediated protection from live influenza virus challenge. We show that migratory cDC2s uniquely carry antigen into the subanatomic regions of the lymph node where Tfh cell priming occurs—the T-B border. This work identifies the DC subset responsible for Tfh cell–dependent antibody responses, particularly when antigen dose is limiting or is encountered at a mucosal site, which could ultimately inform the formulation and delivery of vaccines.
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