IRF4 and IRF8 Act in CD11c+ Cells To Regulate Terminal Differentiation of Lung Tissue Dendritic Cells.
IRF4 and IRF8 Act in CD11c+ Cells To Regulate Terminal Differentiation of Lung Tissue Dendritic Cells.
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DOI：
10.4049/jimmunol.1501870
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发表时间：
2016-02-15
期刊：
影响因子：
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通讯作者：
Kovats S
中科院分区：
文献类型：
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作者：
Bajaña S;Turner S;Paul J;Ainsua-Enrich E;Kovats S
树突状细胞（Dendritic cells，DCs）在肺、皮肤等屏障组织中启动免疫应答。传统的DC亚群，CD 11b-（cDC 1 s）或CD 11b+（cDC 2 s），通过涉及IRF 4和IRF 8的不同转录因子网络产生，并且专门用于独特的功能反应。使用在CD 11 c+细胞中缺失条件性Irf 4或Irf 8等位基因的小鼠，我们确定了在CD 11 c + cDC前体（pre-cDC）中开始的IRF 4或IRF 8缺陷是否改变了肺、真皮和脾中成熟DC或pre-DC的稳态。CD 11 c-cre-Irf 4 −/−小鼠选择性缺乏肺驻留的CD 11 chiCD 11b +SIRPα+ CD 24 + DC亚群，但不缺乏其他肺CD 11b + DC或肺泡巨噬细胞。CD 11b + CD 4+脾DC的数量减少，但CD 11b+真皮DC的数量没有减少，表明肺和真皮中的cDC 2通过不同的途径发育。Irf 4缺陷并没有改变cDC 1的数量。CD 11 c-cre-Irf 8 −/−小鼠缺乏肺驻留的CD 103 + DC和脾CD 8 α+ DC，但具有增加的IRF 4依赖性DC。这与Irf 8 −/− pre-cDC数量减少相关，其中含有升高的IRF 4，表明Irf 8缺陷转移了pre-cDC的命运。对Irf 4和Irf 8单倍不足小鼠的分析表明，虽然一个Irf 4等位基因足以促进肺cDC 2的发育，但肺cDC 1的分化需要两个功能性Irf 8等位基因。因此，IRF 8和IRF 4在pre-cDC中起作用以指导肺和脾中cDC 1和cDC 2亚群的终末分化。这些数据表明，IRF 4或IRF 8水平的遗传多态性或环境因素导致的变化将支配组织DC数量，因此调节DC功能反应的大小。
Dendritic cells (DCs) initiate immune responses in barrier tissues including lung and skin. Conventional DC subsets, CD11b− (cDC1s) or CD11b+ (cDC2s), arise via distinct networks of transcription factors involving IRF4 and IRF8 and are specialized for unique functional responses. Using mice in which a conditional Irf4 or Irf8 allele is deleted in CD11c+ cells, we determined if IRF4 or IRF8 deficiency beginning in CD11c+ cDC precursors (pre-cDCs) changed the homeostasis of mature DCs or pre-DCs in the lung, dermis and spleen. CD11c-cre-Irf4−/− mice selectively lacked a lung-resident CD11chiCD11b+SIRPα+CD24+ DC subset, but not other lung CD11b+ DCs or alveolar macrophages. Numbers of CD11b+CD4+ splenic DCs, but not CD11b+ dermal DCs, were reduced, indicating cDC2s in the lung and dermis develop via different pathways. Irf4 deficiency did not alter numbers of cDC1s. CD11c-cre-Irf8−/− mice lacked lung-resident CD103+ DCs and splenic CD8α+ DCs, yet harbored increased IRF4-dependent DCs. This correlated with a reduced number of Irf8−/− pre-cDCs, which contained elevated IRF4, suggesting that Irf8 deficiency diverts pre-cDC fate. Analyses of Irf4 and Irf8 haploinsufficient mice showed that while one Irf4 allele was sufficient for lung cDC2 development, two functional Irf8 alleles were required for differentiation of lung cDC1s. Thus, IRF8 and IRF4 act in pre-cDCs to direct the terminal differentiation of cDC1 and cDC2 subsets in the lung and spleen. These data suggest that variation in IRF4 or IRF8 levels resulting from genetic polymorphisms or environmental cues will govern tissue DC numbers and therefore regulate the magnitude of DC functional responses.