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诱导共刺激分子通过下调Krüppel样因子2来维持滤泡辅助性T细胞表型。

ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2.

作者信息

Weber Jan P, Fuhrmann Franziska, Feist Randi K, Lahmann Annette, Al Baz Maysun S, Gentz Lea-Jean, Vu Van Dana, Mages Hans W, Haftmann Claudia, Riedel René, Grün Joachim R, Schuh Wolfgang, Kroczek Richard A, Radbruch Andreas, Mashreghi Mir-Farzin, Hutloff Andreas

机构信息

Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.

Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.

出版信息

J Exp Med. 2015 Feb 9;212(2):217-33. doi: 10.1084/jem.20141432. Epub 2015 Feb 2.

DOI:10.1084/jem.20141432
PMID:25646266
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4322049/
Abstract

The co-stimulators ICOS (inducible T cell co-stimulator) and CD28 are both important for T follicular helper (TFH) cells, yet their individual contributions are unclear. Here, we show that each molecule plays an exclusive role at different stages of TFH cell development. While CD28 regulated early expression of the master transcription factor Bcl-6, ICOS co-stimulation was essential to maintain the phenotype by regulating the novel TFH transcription factor Klf2 via Foxo1. Klf2 directly binds to Cxcr5, Ccr7, Psgl-1, and S1pr1, and low levels of Klf2 were essential to maintain this typical TFH homing receptor pattern. Blocking ICOS resulted in relocation of fully developed TFH cells back to the T cell zone and reversion of their phenotype to non-TFH effector cells, which ultimately resulted in breakdown of the germinal center response. Our study describes for the first time the exclusive role of ICOS and its downstream signaling in the maintenance of TFH cells by controlling their anatomical localization in the B cell follicle.

摘要

共刺激分子ICOS（诱导性T细胞共刺激分子）和CD28对滤泡辅助性T（TFH）细胞均很重要，但其各自的作用尚不清楚。在此，我们表明每个分子在TFH细胞发育的不同阶段发挥着独特作用。虽然CD28调节主转录因子Bcl-6的早期表达，但ICOS共刺激对于通过Foxo1调节新型TFH转录因子Klf2来维持该表型至关重要。Klf2直接结合Cxcr5、Ccr7、Psgl-1和S1pr1，低水平的Klf2对于维持这种典型的TFH归巢受体模式至关重要。阻断ICOS导致完全发育的TFH细胞重新回到T细胞区，并使其表型逆转为非TFH效应细胞，最终导致生发中心反应的瓦解。我们的研究首次描述了ICOS及其下游信号在通过控制TFH细胞在B细胞滤泡中的解剖定位来维持TFH细胞方面的独特作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/daf5a39577fe/JEM_20141432_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/c5b21d64bbcc/JEM_20141432_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/1e523061cc0e/JEM_20141432_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/3eafdb5795f1/JEM_20141432_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/29c055bb597e/JEM_20141432_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/7e5525aaaa93/JEM_20141432_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/095076be1456/JEM_20141432_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/35a435abc79a/JEM_20141432_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/d691dfada85e/JEM_20141432R_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/2788271363f5/JEM_20141432_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/daf5a39577fe/JEM_20141432_Fig10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/c5b21d64bbcc/JEM_20141432_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/1e523061cc0e/JEM_20141432_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/3eafdb5795f1/JEM_20141432_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/29c055bb597e/JEM_20141432_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/7e5525aaaa93/JEM_20141432_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/095076be1456/JEM_20141432_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/35a435abc79a/JEM_20141432_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/d691dfada85e/JEM_20141432R_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/2788271363f5/JEM_20141432_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c3e9/4322049/daf5a39577fe/JEM_20141432_Fig10.jpg

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