The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells.
The inducible costimulator (ICOS) is critical for the development of human T(H)17 cells.
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DOI：
10.1126/scitranslmed.3000448
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发表时间：
2010-10-27
影响因子：
17.1
通讯作者：
June CH
中科院分区：
文献类型：
--
作者：
Paulos CM;Carpenito C;Plesa G;Suhoski MM;Varela-Rohena A;Golovina TN;Carroll RG;Riley JL;June CH
人辅助性T细胞17（TH 17）调节宿主防御、自身免疫和肿瘤免疫。虽然已经鉴定了控制人TH 17细胞发育的细胞因子，但是对于TH 17细胞生成重要的共刺激分子是未知的。在这里，我们发现，诱导型共刺激分子（ICOS）是人TH 17细胞的分化和扩增的关键。人脐带血中含有一个CD 161 + CD 4 +T细胞亚群，它们是最近从胸腺中迁移出来的，组成性表达ICOS，并通过ICOS信号转导被标记为TH 17细胞。ICOS刺激诱导这些细胞中的c-MAF、RORC 2和T-bet表达，导致与用CD 28刺激的细胞相比，白细胞介素-21（IL-21）、IL-17和干扰素-γ（IFN-γ）的分泌增加。相反，CD 28连接废除ICOS共刺激，抑制RORC 2表达，同时促进芳烃受体的表达，这导致与用ICOS刺激的细胞相比，IL-17的分泌减少，IL-22的产生增加。此外，ICOS促进了IL-17+IFN-γ+人T细胞的稳健扩增，并且这些细胞在过继转移到携带大的人肿瘤的小鼠中后的抗肿瘤活性上级于用CD 28扩增的细胞的抗肿瘤活性。ICOS扩增细胞的治疗效果与增强的功能和体内植入相关。这些发现揭示了ICOS信号传导在人类TH 17细胞的产生和维持中的重要作用，并表明该途径的组分可以在治疗上靶向治疗癌症或慢性感染，相反，该途径的中断可能在多发性硬化症和其他自身免疫综合征中具有实用性。这些发现为设计新的肿瘤免疫治疗临床试验提供了理论基础。
Human T helper 17 (TH17) cells regulate host defense, autoimmunity, and tumor immunity. Although cytokines that control human TH17 cell development have been identified, the costimulatory molecules important for TH17 cell generation are unknown. Here, we found that the inducible costimulator (ICOS) was critical for the differentiation and expansion of human TH17 cells. Human cord blood contained a subset of CD161+CD4+T cells that were recent emigrants from the thymus, expressed ICOS constitutively, and were imprinted as TH17 cells through ICOS signaling. ICOS stimulation induced c-MAF, RORC2, and T-bet expression in these cells, leading to increased secretion of interleukin-21 (IL-21), IL-17, and interferon-γ (IFN-γ) compared with cells stimulated with CD28. Conversely, CD28 ligation abrogated ICOS costimulation, dampening RORC2 expression while promoting the expression of the aryl hydrocarbon receptor, which led to reduced secretion of IL-17 and enhanced production of IL-22 compared with cells stimulated with ICOS. Moreover, ICOS promoted the robust expansion of IL-17+IFN-γ+ human T cells, and the antitumor activity of these cells after adoptive transfer into mice bearing large human tumors was superior to that of cells expanded with CD28. The therapeutic effectiveness of ICOS-expanded cells was associated with enhanced functionality and engraftment in vivo. These findings reveal a vital role for ICOS signaling in the generation and maintenance of human TH17 cells and suggest that components of this pathway could be therapeutically targeted to treat cancer or chronic infection and, conversely, that interruption of this pathway may have utility in multiple sclerosis and other autoimmune syndromes. These findings have provided the rationale for designing new clinical trials for tumor immunotherapy.
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影响因子：
30.5
作者：
Acosta-Rodriguez, Eva V.;Napolitani, Giorgio;Sallusto, Federica
通讯作者：
Sallusto, Federica
人白细胞介素17产生的细胞起源于CD161+ CD4+ T细胞前体。
影响因子：
15.3
作者：
Cosmi, Lorenzo;De Palma, Raffaele;Santarlasci, Veronica;Maggi, Laura;Capone, Manuela;Frosali, Francesca;Rodolico, Gabriella;Querci, Valentina;Abbate, Gianfranco;Angeli, Roberta;Berrino, Liberato;Fambrini, Massimiliano;Caproni, Marzia;Tonelli, Francesco;Lazzeri, Elena;Parronchi, Paola;Liotta, Francesco;Maggi, Enrico;Romagnani, Sergio;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
CD127表达与FOXP3和人类CD4+ T Reg细胞的抑制功能成反比。
DOI：
10.1084/jem.20060772
发表时间：
2006-07-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
通讯作者：
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影响因子：
30.5
作者：
通讯作者：
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影响因子：
30.5
作者：
Manel, Nicolas;Unutmaz, Derya;Littman, Dan R.
通讯作者：
Littman, Dan R.