title: ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2.
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.
authors: 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.
authors: Jan P
authors: JP
authors: Weber
authors: 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.
authors: Franziska
authors: F
authors: Fuhrmann
authors: 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.
authors: Randi K
authors: RK
authors: Feist
authors: 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.
authors: Annette
authors: A
authors: Lahmann
authors: 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.
authors: Maysun S
authors: MS
authors: Al Baz
authors: 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.
authors: Lea-Jean
authors: LJ
authors: Gentz
authors: 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.
authors: Dana
authors: D
authors: Vu Van
authors: Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.
authors: Hans W
authors: HW
authors: Mages
authors: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany.
authors: Claudia
authors: C
authors: Haftmann
authors: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany.
authors: René
authors: R
authors: Riedel
authors: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany.
authors: Joachim R
authors: JR
authors: Grün
authors: Division of Molecular Immunology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany.
authors: Wolfgang
authors: W
authors: Schuh
authors: Molecular Immunology, Robert Koch Institute, 13353 Berlin, Germany.
authors: Richard A
authors: RA
authors: Kroczek
authors: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany.
authors: Andreas
authors: A
authors: Radbruch
authors: Chronic Immune Reactions, Cell Biology, and Bioinformatics, German Rheumatism Research Centre, a Leibniz Institute, 10117 Berlin, Germany.
authors: Mir-Farzin
authors: MF
authors: Mashreghi
authors: 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.
authors: Andreas
authors: A
authors: Hutloff
mesh_terms: D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014066:Palatine Tonsil / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D054400:Receptors, CCR7 / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: D018106:CD28 Antigens; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D054400:Receptors, CCR7; D054380:Receptors, CXCR5
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