NF-κB regulates PD-1 expression in macrophages.
NF-κB regulates PD-1 expression in macrophages.
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DOI：
10.4049/jimmunol.1402550
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发表时间：
2015-05-01
期刊：
影响因子：
--
通讯作者：
Boss JM
中科院分区：
文献类型：
--
作者：
Bally AP;Lu P;Tang Y;Austin JW;Scharer CD;Ahmed R;Boss JM
程序性细胞死亡-1（PD-1）3负责慢性病毒感染期间的T细胞耗竭，并在激活后在多种免疫细胞上表达。尽管其重要性，但在CD 8 T细胞以外的细胞类型中调节PD-1的机制尚不清楚。在此，探索了诱导CD 4 T细胞、巨噬细胞和B细胞中PD-1表达的分子机制。在CD 4 T细胞中，TCR刺激后的PD-1诱导需要NFAT，因为钙调磷酸酶/NFAT途径抑制剂环孢霉素A（CsA）能够以与CD 8 T细胞中所见相似的方式阻断PD-1诱导。相比之下，LPS而不是PMA和离子霉素刺激能够以对CsA介导的抑制不敏感的方式诱导巨噬细胞中的PD-1表达。B细胞可以使用这两种途径，尽管PMA和离子霉素的PD-1表达水平最高。NF-κB结合位点位于保守区C基因上游，是NF-κB依赖性PD-1基因激活所必需的。染色质免疫沉淀显示，在用LPS刺激巨噬细胞后，NF-κB p65与该区域结合。PD-1诱导与可接近染色质的组蛋白修饰特征相关;然而，与CD 8 T细胞相反，巨噬细胞中的保守区B在刺激和PD-1表达后不会丢失CpG甲基化。TLR / NF-κB信号传导与PD-1诱导的联系表明，微生物感染在操纵免疫抑制反应方面可能具有机会优势。
Programmed Cell Death-1 (PD-1)3 is responsible for T cell exhaustion during chronic viral infections and is expressed on a variety of immune cells following activation. Despite its importance, the mechanisms that regulate PD-1 in cell types other than CD8 T cells are poorly defined. Here, the molecular mechanism(s) for inducing PD-1 expression in CD4 T cells, macrophages, and B cells was explored. In CD4 T cells, PD-1 induction following TCR stimulation required NFAT, as the Calcineurin/NFAT pathway inhibitor cyclosporine A (CsA) was able to block PD-1 induction in a manner similar to that seen in CD8 T cells. By contrast, LPS but not PMA and Ionomycin stimulation was able to induce PD-1 expression in macrophages in a manner insensitive to CsA-mediated inhibition. B cells could use both pathways, although the levels of PD-1 expression were highest with PMA and Ionomycin. NF-κB binding site located upstream of the gene in Conserved Region-C was required for NF-κB dependent PD-1 gene activation in macrophages. Chromatin immunoprecipitation showed NF-κB p65 binding to this region following stimulation of macrophages with LPS. PD-1 induction was associated with histone modifications characteristic of accessible chromatin; however, in contrast to CD8 T cells, Conserved Region B in macrophages did not lose CpG methylation upon stimulation and PD-1 expression. The linkage of TLR / NF-κB signaling to the induction of PD-1 suggest the possibility of an opportunistic advantage to microbial infections in manipulating immune inhibitory responses.
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影响因子：
30.5
作者：
Butler, Noah S.;Moebius, Jacqueline;Pewe, Lecia L.;Traore, Boubacar;Doumbo, Ogobara K.;Tygrett, Lorraine T.;Waldschmidt, Thomas J.;Crompton, Peter D.;Harty, John T.
通讯作者：
Harty, John T.
影响因子：
32.4
作者：
Honda T;Egen JG;Lämmermann T;Kastenmüller W;Torabi-Parizi P;Germain RN
通讯作者：
Germain RN
影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
影响因子：
4.8
作者：
Guo, Z;Boekhoudt, GH;Boss, JM
通讯作者：
Boss, JM