Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release
Redirection of allergen-specific TH2 responses by a modified adenine through Toll-like receptor 7 interaction and IL-12/IFN release
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DOI：
10.1016/j.jaci.2006.05.027
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发表时间：
2006-08-01
影响因子：
14.2
通讯作者：
Parronchi, Paola
中科院分区：
文献类型：
--
作者：
Fili, Lucia;Ferri, Simona;Parronchi, Paola
背景：Toll样受体（TLRs）的天然或合成配体，如含CpG的寡脱氧核苷酸和咪唑喹啉，通过诱导天然免疫细胞释放细胞因子来影响抗原特异性人T淋巴细胞的功能表型。
目的：在体外研究替代腺嘌呤（SAs）影响抗原呈递细胞并改变特异性人T(H)2细胞功能表型的能力。
方法：通过实时定量PCR、流式细胞术和酶联免疫吸附测定（ELISAs）评估在有或无修饰腺嘌呤存在的情况下获得的半抗原和过敏原特异性T细胞系的功能特征。通过对HEK293细胞进行核转染来评估TLRs的激活情况。
结果：化学结构上与腺嘌呤相关且在2 -、8 -和9 -位有取代的合成杂环（SA - 2），而不是其缺少2 -和8 -位取代的相关衍生物，刺激CD14(+)细胞产生大量白细胞介素 - 12（IL - 12）、白细胞介素 - 10（IL - 10）、肿瘤坏死因子 -α（TNF -α）和白细胞介素 - 6（IL - 6），以及刺激血液树突状细胞抗原（BDCA）- 4(+)浆细胞样树突状细胞产生干扰素 -α（IFN -α）和趋化因子（C - X - C基序）配体10（CXCL10）。由SA - 2与TLR7结合介导的核因子κB依赖的信号通路是这些效应的原因。SA - 2还使屋尘螨第1组或阿莫西林特异性T(H)2细胞在体外分化向T(H)1/T(H)0表型转变，同时GATA - 3下调，T细胞中表达的T - box转录因子上调。
结论：腺嘌呤主链的关键取代赋予激活TLR7的能力，诱导调节性细胞因子的产生，从而能够将人过敏原特异性T(H)2细胞转变为T(H)1/T(H)0表型。
临床意义：经过适当修饰的腺嘌呤可作为有效的佐剂，用于开发过敏性疾病的新型免疫治疗策略。
Background: Natural or synthetic ligands of Toll-like receptors (TLRs), such as CpG-containing oligodeoxynucleotides and imidazoquinolines, affect the functional phenotype of antigen-specific human T lymphocytes by inducing cytokine release by cells of the innate immunity.Objective: In vitro investigation of the ability of substitute adenines (SAs) to affect antigen-presenting cells and shift the functional phenotype of specific human T(H)2 cells was performed.Methods: The functional profile of hapten- and allergen-specific T-cell lines obtained in the absence or presence of modified adenines was assessed by means of quantitative real-time PCR, flow cytometry, and ELISAs. Activation of TLRs was evaluated by means of nucleofection of HEK293 cells.Results: The synthetic heterocycle, chemically related to adenine with substitution in positions 2-, 8-, and 9- (SA-2), but not its related derivative lacking 2- and 8- substitutions, stimulated the production of high amounts of IL-12, IL-10, TNF-alpha, and IL-6 by CD14(+) cells and IFN-alpha and CXCL10 by blood dendritic cell antigen (BDCA)-4(+) plasmacytoid dendritic cells. A nuclear factor kappa B-dependent signaling pathway mediated by SA-2 ligation of TLR7 was responsible for these effects. SA-2 also redirected the in vitro differentiation of either Dermatophagoides pteronyssinus group 1 or amoxicillin-specific TH2 cells toward the T(H)1/T(H)0 phenotype, with parallel downregulation of GATA-3 and upregulation of T-box expressed in T cells transcription factors.Conclusion: Critical substitutions of the adenine backbone confer the ability to activate TLR7, inducing the production of modulatory cytokines able to shift human allergen-specific T(H)2 cells to a T(H)1/T(H)0 phenotype.Clinical implications: Appropriately modified adenines might be used as effective adjuvants for the development of novel immunotherapeutic strategies of allergic disorders.