Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation
Transcription factor IRF4 determines germinal center formation through follicular T-helper cell differentiation
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DOI：
10.1073/pnas.1205834109
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发表时间：
2012-05-29
影响因子：
11.1
通讯作者：
Lohoff, Michael
中科院分区：
文献类型：
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作者：
Bollig, Nadine;Bruestle, Anne;Lohoff, Michael
滤泡t辅助细胞（T-FH）与GL7(+)CD95（+）生发中心（GC） B细胞协同诱导抗体成熟。本文中，我们发现转录因子IRF4是T-FH细胞分化和GC形成的固有先决条件。用蛋白质免疫或感染利什曼原虫后，ifn调节因子-4 （Irf4(-/-)）小鼠的引流淋巴结（LNs）缺乏GCs和GC B细胞，尽管初始增生正常。幼稚Irf4（-/-）小鼠的Peyer’s斑块中也没有GCs。因此，LNs和Peyer's斑块内的CD4(+) T细胞不能表达T- fh关键转录因子b细胞淋巴瘤-6和其他T- fh相关分子。在慢性利什曼病中，引流的Irf4(-/-) ln由于大量细胞死亡而消失。WT CD4(+) T细胞或少量L. major引物的WT T- fh细胞过继转移可重建GC形成、GC b细胞分化和LN细胞存活。为了支持t细胞固有的IRF4活性，IRF4 (-/-) T-FH细胞的分化并没有通过靠近转移的WT T-FH细胞来挽救。结合其在浆细胞成熟和类转换过程中已知的B谱系特异性作用，我们的研究将IRF4置于针对t细胞依赖性抗原的抗体产生的中心。
Follicular T-helper (T-FH) cells cooperate with GL7(+)CD95(+) germinal center (GC) B cells to induce antibody maturation. Herein, we identify the transcription factor IRF4 as a T-cell intrinsic precondition for T-FH cell differentiation and GC formation. After immunization with protein or infection with the protozoon Leishmania major, draining lymph nodes (LNs) of IFN-regulatory factor-4 (Irf4(-/-)) mice lacked GCs and GC B cells despite developing normal initial hyperplasia. GCs were also absent in Peyer's patches of naive Irf4(-/-) mice. Accordingly, CD4(+) T cells within the LNs and Peyer's patches failed to express the T-FH key transcription factor B-cell lymphoma-6 and other T-FH-related molecules. During chronic leishmaniasis, the draining Irf4(-/-) LNs disappeared because of massive cell death. Adoptive transfer of WT CD4(+) T cells or few L. major primed WT T-FH cells reconstituted GC formation, GC B-cell differentiation, and LN cell survival. In support of a T-cell intrinsic IRF4 activity, Irf4(-/-) T-FH cell differentiation was not rescued by close neighborhood to transferred WT T-FH cells. Together with its known B lineage-specific roles during plasma cell maturation and class switch, our study places IRF4 in the center of antibody production toward T-cell-dependent antigens.