Amplifying IFN-γ Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity.
Amplifying IFN-γ Signaling in Dendritic Cells by CD11c-Specific Loss of SOCS1 Increases Innate Immunity to Infection while Decreasing Adaptive Immunity.
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DOI：
10.4049/jimmunol.1700909
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发表时间：
2018-01-01
期刊：
影响因子：
--
通讯作者：
Crittenden MR
中科院分区：
文献类型：
--
作者：
Alice AF;Kramer G;Bambina S;Baird JR;Bahjat KS;Gough MJ;Crittenden MR
虽然预防性疫苗提供针对感染因子的保护性体液免疫，但引发有效的CD8 T细胞应答的疫苗是塑造和驱动针对癌症和细胞内感染的细胞免疫的有价值的工具。特别是，IFNγ极化的细胞毒性CD8 T细胞免疫被认为是针对细胞内抗原的保护性免疫的最佳选择。SOCS1是TLR和细胞因子受体信号传导的交叉功能负调节剂，通过降解受体信号传导复合物。我们假设树突状细胞中SOCS1的缺失将通过增强IFNγ导向的免疫应答来改善T细胞应答。我们使用重组单核细胞增生李斯特菌疫苗平台测试了这一假设，该疫苗平台靶向小鼠中的CD11c+树突状细胞，其中SOCS1在所有CD11c+细胞中选择性缺失。出乎意料的是，在CD11c+细胞中缺乏SOCS1表达的小鼠中，我们观察到CD8+ T细胞对单核细胞增多性李斯特菌疫苗的应答降低。在CD11c+细胞中缺乏SOCS1表达的小鼠中，NK细胞应答也降低，但不能解释CD8+ T细胞免疫的缺陷。我们发现，缺乏SOCS1表达的DC在体外驱动抗原特异性CD8+ T细胞扩增中具有功能，但在体内感染后，这一过程是有缺陷的。相反，单核细胞衍生的先天性TNFα和iNOS产生DC（TipDC）主导了抗菌反应。因此，CD11c+细胞中SOCS1的缺失通过增加先天性应答同时降低对感染性抗原的抗原特异性适应性应答而使对感染的免疫应答的平衡发生倾斜。
While prophylactic vaccines provide protective humoral immunity against infectious agents, vaccines that elicit potent CD8 T cell responses are valuable tools to shape and drive cellular immunity against cancer and intracellular infection. In particular, IFNγ-polarized cytotoxic CD8 T cell immunity is considered optimal for protective immunity against intracellular antigens. SOCS1 is a cross-functional negative regulator of TLR and cytokine receptor signaling via degradation of the receptor-signaling complex. We hypothesized that loss of SOCS1 in dendritic cells would improve T cell responses by accentuating IFNγ-directed immune responses. We tested this hypothesis using a recombinant Listeria monocytogenes vaccine platform that targets CD11c+ dendritic cells in mice where SOCS1 is selectively deleted in all CD11c+ cells. Unexpectedly, in mice lacking SOCS1 expression in CD11c+ cells, we observed a decrease in CD8+ T cell response to the Listeria monocytogenes vaccine. NK cell responses were also decreased in mice lacking SOCS1 expression in CD11c+ cells, but did not explain the defect in CD8+ T cell immunity. We found that DC lacking SOCS1 expression were functional in driving antigen-specific CD8+ T cell expansion in vitro, but that this process was defective following infection in vivo. Instead monocyte-derived innate TNFα and iNOS-producing DC (TipDC) dominated the anti-bacterial response. Thus, loss of SOCS1 in CD11c+ cells skewed the balance of immune response to infection by increasing innate responses while decreasing antigen-specific adaptive responses to infectious antigens.
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影响因子：
15.3
作者：
Bonifaz, L;Bonnyay, D;Mahnke, K;Rivera, M;Nussenzweig, MC;Steinman, RM
通讯作者：
Steinman, RM
影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
6.7
作者：
Archer KA;Durack J;Portnoy DA
通讯作者：
Portnoy DA
影响因子：
3.1
作者：
Bahjat, Keith S.;Liu, Weiqun;Brockstedt, Dirk G.
通讯作者：
Brockstedt, Dirk G.
影响因子：
64.5
作者：
Marine, JC;Topham, DJ;Ihle, JN
通讯作者：
Ihle, JN