title: Leukocyte β7 integrin targeted by Krüppel-like factors.
abstract: Constitutive expression of Krüppel-like factor 3 (KLF3, BKLF) increases marginal zone (MZ) B cell numbers, a phenotype shared with mice lacking KLF2. Ablation of KLF3, known to interact with serum response factor (SRF), or SRF itself, results in fewer MZ B cells. It is unknown how these functional equivalences result. In this study, it is shown that KLF3 acts as transcriptional repressor for the leukocyte-specific integrin β7 (Itgb7, Ly69) by binding to the β7 promoter, as revealed by chromatin immunoprecipitation. KLF2 overexpression antagonizes this repression and also binds the β7 promoter, indicating that these factors may compete for target sequence(s). Whereas β7 is identified as direct KLF target, its repression by KLF3 is not connected to the MZ B cell increase because β7-deficient mice have a normal complement of these and the KLF3-driven increase still occurs when β7 is deleted. Despite this, KLF3 overexpression abolishes lymphocyte homing to Peyer's patches, much like β7 deficiency does. Furthermore, KLF3 expression alone overcomes the MZ B cell deficiency when SRF is absent. SRF is also dispensable for the KLF3-mediated repression of β7. Thus, despite the shared phenotype of KLF3 and SRF-deficient mice, cooperation of these factors appears neither relevant for the formation of MZ B cells nor for the regulation of β7. Finally, a potent negative regulatory feedback loop limiting KLF3 expression is shown in this study, mediated by KLF3 directly repressing its own gene promoter. In summary, KLFs use regulatory circuits to steer lymphocyte maturation and homing and directly control leukocyte integrin expression.
authors.affiliation: Division of Immunology (3/3), Paul-Ehrlich-Institut, 63225 Langen, Germany;
authors.forename: Melanie
authors.initials: M
authors.lastname: Alles
authors.affiliation: Department of Biomedicine, Laboratory of Developmental Immunology, 4058 Basel, Switzerland; Basel University Children's Hospital, 4031 Basel, Switzerland;
authors.forename: Gleb
authors.initials: G
authors.lastname: Turchinovich
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030;
authors.forename: Pumin
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger-Center, University of Erlangen-Nürnberg, 91054 Erlangen, Germany;
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuh
authors.affiliation: INSERM U743, Montreal, Quebec H2X 1P1, Canada; and INSERM ADR Paris V Saint Anne, 75014 Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Agenès
authors.affiliation: Division of Immunology (3/3), Paul-Ehrlich-Institut, 63225 Langen, Germany; kirjo@pei.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kirberg
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D018845:CD11 Antigens / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000276:immunology; D039001:Integrin alpha Chains / Q000096:biosynthesis; D039641:Integrin beta Chains / Q000235:genetics*; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D038041:Lymphopoiesis / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010581:Peyer's Patches / Q000276:immunology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D026362:Serum Response Factor / Q000235:genetics
chemical_list: D018845:CD11 Antigens; D004268:DNA-Binding Proteins; D039001:Integrin alpha Chains; D039641:Integrin beta Chains; C498314:Klf2 protein, mouse; C529780:Klf3 protein, mouse; D051741:Kruppel-Like Transcription Factors; D026362:Serum Response Factor; C527123:integrin alphaD, mouse; C091368:integrin beta7