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.

Krüppel-Like Factors in Vascular Inflammation: Mechanistic Insights and Therapeutic Potential

“…While KLF2 is associated with a B1 B-cell differentiation pattern (with lower levels associated with follicular and marginal zone cells), KLF3 expression favors marginal zone B-cell development ( 129 ). Additionally, KLF2 and KLF3 compete for occupancy of the Itgb7 promoter: while KLF2 promotes expression of Itgb7 and, thus, migration, KLF3 leads to downregulation of Itgb7 and impaired homing ability of lymphocytes ( 130 ). Interestingly, KLF2 and 3 differentially regulate KLF3 expression itself.…”

“…Interestingly, KLF2 and 3 differentially regulate KLF3 expression itself. KLF3 negatively regulates its own expression through direct binding to the KLF3 promoter ( 130 ). Conversely, loss of KLF2 in B cells results in decreased expression of KLF3 (i.e., KLF2 increases KLF3 expression) ( 128 ).…”

Bovine Neonatal Pancytopenia-Associated Alloantibodies Recognize Individual Bovine Leukocyte Antigen 1 Alleles

“…5 × 10 6 Plat-E packaging cells (Cell Biolabs Inc.), stably expressing MoMLV-gag-pol and env, were transfected with plasmid by CaCl 2 transfection, as described ( 12 ). After approximately 15 h, the medium was exchanged with fresh SF-IMDM containing 10% FCS, and after 24 h the supernatant containing virus particles was harvested.…”

Krüppel-like Factor 2 (KLF2) in Immune Cell Migration

“…KLF2-deficient FO B cells exhibit a loss of L-Selectin and Itgβ7 expression. Both, L-Selectin and Itgβ7 are regulated by the direct binding of KLF2 to the respective promoters (Figures 1 and 2) [58,61]. Interestingly, S1PR1 expression is not altered in KLF2-deficient FO B cells [19,21], indicating that S1PR1 expression is regulated independently of KLF2 in FO B cells.…”

“…For example, CD8 + T cell stimulation by CD103 + mucosal dendritic cells, causes T cells to migrate to the mucosal inductive (i.e., Peyer's Patches) or effector (i.e., Lamina Propria) sites by Itgα4β7 and CCR9 [27]. In this context, KLF2 plays a major role, as it is capable to directly target the Itgβ7 promotor [61].…”