T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.
T follicular helper cells restricted by IRF8 contribute to T cell-mediated inflammation.
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DOI：
10.1016/j.jaut.2018.09.001
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发表时间：
2019-01
影响因子：
12.8
通讯作者：
Xiong H
中科院分区：
文献类型：
--
作者：
Zhang R;Qi CF;Hu Y;Shan Y;Hsieh YP;Xu F;Lu G;Dai J;Gupta M;Cui M;Peng L;Yang J;Xue Q;Chen-Liang R;Chen K;Zhang Y;Fung-Leung WP;Mora JR;Li L;Morse HC 3rd;Ozato K;Heeger PS;Xiong H
滤泡辅助性T细胞（TFH）是成熟的生殖中心（GC）B细胞的调节者，TFH是否具有独立于B细胞的致病潜能尚不清楚。本研究以TFH细胞体外诱导分化、体内T细胞移植结肠炎动物模型和炎症性肠病（IBD）患者肠道组织为研究对象，采用流式细胞术、ChIP、ChIP-sequencing、WB、ELISA和PCR等方法，对TFH及其在结肠炎发生发展中的作用进行了研究。在此，我们证明了患者的肠组织和从患有结肠炎的初始CD 4 + T细胞的Rag 1 −/−受体获得的结肠组织，各自过表达TFH相关基因产物。将幼稚Bcl 6-/-CD 4 + T细胞过继转移到Rag 1-/-受体小鼠中，消除了结肠炎的发生，并限制了体内TFH的分化，证明了机制上的联系。与此相反，T细胞缺乏干扰素调节因子8（IRF 8）导致增强TFH诱导在体外和体内。功能研究表明，将IRF 8缺陷型CD 4 + T细胞过继转移到Rag 1 −/−受体中会加剧与肠道TFH相关基因表达增加相关的结肠炎发展，而Irf 8 −/−/Bcl 6 −/− CD 4 + T细胞则会消除结肠炎，这表明IRF 8调节的TFH可以直接导致结肠炎症。分子分析显示，IRF 8通过抑制TF IRF 4的转录和反式激活来抑制TFH分化，这也是已知的TFH诱导所必需的。我们的文献表明，IRF 8调节的TFH可以作为B细胞非依赖性的、致病性的结肠炎介质发挥作用，这表明靶向TFH可以有效治疗IBD。
The follicular helper T cell (TFH) are established regulators of germinal center (GC) B cells, whether TFH have pathogenic potential independent of B cells is unknown. Based on in vitro TFH cell differentiation, in vivo T cell transfer animal colitis model, and intestinal tissues of inflammatory bowel disease (IBD) patients, TFH and its functions in colitis development were analyzed by FACS, ChIP, ChIP-sequencing, WB, ELISA and PCR. Herein we demonstrate that intestinal tissues of patients and colon tissues obtained from Rag1−/− recipients of naïve CD4+ T cells with colitis, each over-express TFHassociated gene products. Adoptive transfer of naïve Bcl6−/− CD4+ T cells into Rag1−/− recipient mice abrogated development of colitis and limited TFH differentiation in vivo, demonstrating a mechanistic link. In contrast, T cell deficiency of interferon regulatory factor 8 (IRF8) resulted in augmentation of TFH induction in vitro and in vivo. Functional studies showed that adoptive transfer of IRF8 deficient CD4+ T cells into Rag1−/− recipients exacerbated colitis development associated with increased gut TFH-related gene expression, while Irf8−/−/Bcl6−/− CD4+ T cells abrogated colitis, together indicating that IRF8-regulated TFH can directly cause colon inflammation. Molecular analyses revealed that IRF8 suppresses TFH differentiation by inhibiting transcription and transactivation of the TF IRF4, which is also known to be essential for TFH induction. Our documentation showed that IRF8-regulated TFH can function as B-cell-independent, pathogenic, mediators of colitis suggests that targeting TFH could be effective for treatment of IBD.
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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.
DOI：
10.1038/nrrheum.2012.58
发表时间：
2012-05-01
期刊：
Nature reviews. Rheumatology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1073/pnas.1205834109
发表时间：
2012-05-29
影响因子：
11.1
作者：
Bollig, Nadine;Bruestle, Anne;Lohoff, Michael
通讯作者：
Lohoff, Michael
DOI：
10.4049/jimmunol.1001950
发表时间：
2011-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Feng J;Wang H;Shin DM;Masiuk M;Qi CF;Morse HC 3rd
通讯作者：
Morse HC 3rd
DOI：
10.1084/jem.20111174
发表时间：
2012-02-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Johnston RJ;Choi YS;Diamond JA;Yang JA;Crotty S
通讯作者：
Crotty S