Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells
Type I IFN Contributes to the Phenotype of Unc93b1D34A/D34A Mice by Regulating TLR7 Expression in B Cells and Dendritic Cells
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DOI：
10.4049/jimmunol.1500071
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发表时间：
2016-01-01
影响因子：
4.4
通讯作者：
Miyake, Kensuke
中科院分区：
文献类型：
--
作者：
Fukui, Ryutaro;Kanno, Atsuo;Miyake, Kensuke
TLR 7识别病原体来源的和自身来源的RNA，因此需要用于控制TLR 7应答的调节系统以避免过度活化。Unc 93同系物B1（Unc 93 B1）是TLR 7的调节因子，通过将TLR 7从内质网转运到内溶酶体来控制TLR 7反应。我们之前已经证明Unc 93 B1中的D34 A突变诱导TLR 7的过度活化，并且Unc 93 b1（D34 A/D34 A）小鼠（D34 A小鼠）自发地具有全身性炎症。在这项研究中，我们研究了炎症细胞因子如IFN-γ，IL-17 A和I型IFN的作用，以了解D34 A小鼠表型的机制。CD 4（+）T细胞中IFN-γ和IL-17 A的mRNA增加，但在Ifng（-/-）或Il 17 a（-/-）D34 A小鼠中仍观察到表现为血小板减少和脾肿大的炎性表型。与T细胞衍生的细胞因子相比，Ifnar 1（-/-）D34 A小鼠表现出改善的表型，在B细胞和常规树突状细胞（cDC）中具有较低的TLR 7表达。Ifnar 1（-/-）D34 A小鼠的B细胞中TLR 7的量减少，但CD 8（alpha）（-）cDC中TLR 7（+）细胞的百分比减少。总之，I型IFN以不同的方式维持TLR 7在B细胞和cDC中的表达; TLR 7的总量保持在B细胞中，而TLR 7（+）群体保持在cDC中。我们的研究结果表明，这些TLR 7表达细胞最初被激活，并影响TLR 7依赖性全身炎症。
TLR7 recognizes pathogen-derived and self-derived RNA, and thus a regulatory system for control of the TLR7 response is required to avoid excessive activation. Unc93 homolog B1 (Unc93B1) is a regulator of TLR7 that controls the TLR7 response by transporting TLR7 from the endoplasmic reticulum to endolysosomes. We have previously shown that a D34A mutation in Unc93B1 induces hyperactivation of TLR7, and that Unc93b1(D34A/D34A) mice (D34A mice) have systemic inflammation spontaneously. In this study, we examined the roles of inflammatory cytokines such as IFN-gamma, IL-17A, and type I IFNs to understand the mechanism underlying the phenotype in D34A mice. mRNAs for IFN-gamma and IL-17A in CD4(+) T cells increased, but inflammatory phenotype manifesting as thrombocytopenia and splenomegaly was still observed in Ifng(-/-) or Il17a(-/-) D34A mice. In contrast to T cell derived cytokines, Ifnar1(-/-) D34A mice showed an ameliorated phenotype with lower expression of TLR7 in B cells and conventional dendritic cells (cDCs). The amount of TLR7 decreased in B cells from Ifnar1(-/-) D34A mice, but the percentage of TLR7(+) cells decreased among CD8(alpha)(-) cDCs. In conclusion, type I IFNs maintain expression of TLR7 in B cells and cDCs in different ways; total amount of TLR7 is kept in B cells and TLR7(+) population is retained among cDCs. Our results suggested that these TLR7-expressing cells are activated initially and influence TLR7-dependent systemic inflammation.