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

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

Author information

1
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.
2
Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.
3
Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany.
4
Division of Molecular Immunology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
5
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 hutloff@drfz.de.

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.

PMID:
25646266
PMCID:
PMC4322049
DOI:
10.1084/jem.20141432
[Indexed for MEDLINE]
Free PMC Article

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