Summary of published findings related to Kruppel-like factors in leukocyte biology and disease
| Cell type/factor . | Function/observation . | References . |
|---|---|---|
| T cells | ||
| KLF2 | Expressed in single-positive CD4+ and CD8+ T cells, induced by statins and rapamycin, and rapidly extinguished after T-cell activation via the PI3K/AKT signaling pathway. | 24, 30, 33, 34 |
| Regulates T-cell trafficking by targeting S1P1, CD62L, β7-integrin, and chemokine receptors through both autonomous and nonautonomous mechanisms. | 27, 31, 33, 35–36 | |
| Overexpression in CD8+ effector T cells mimics statins' anti-inflammatory effects and ameliorates CD8+ T cell–mediated myocarditis. | 30 | |
| KLF4 | Expressed in CD8+ T cells where it maintains T-cell quiescence downstream of Ets transcription factor ELF. | 37 |
| Regulates expression of p21 in CD8+ T cells. | ||
| KLF4 promoter is densely methylated in PBMCs from patients with adult T-cell leukemia (ATL) compared with healthy controls. | 42 | |
| Overexpression prevents ATL cell proliferation and induces apoptosis. | ||
| KLF10 | Expressed highly in T regulatory cells than CD4+CD25− T cells. | 45, 46 |
| Induced in response to TGF-β1 and the Itch ubiquitin ligase. | ||
| Targets both TGF-β1 and Foxp3 promoters to promote T reg cell differentiation as part of a positive feedback loop. | 45 | |
| Promotes T reg cell suppressor function independent of Foxp3 by increasing the expression of TGF-β1. | ||
| Inhibits Th1 and Th2 differentiation pathways. | ||
| Adoptive transfer of KLF10−/− T cells accelerates atherosclerosis in ApoE−/− scid/scid mice. | ||
| KLF10−/− 'TGF-β1 in vitro converted T regs fail to suppress airway inflammation. | 46 | |
| Genetic variant in KLF10 3′-UTR associated with type 2 diabetes. | 47 | |
| KLF13 | Expressed in response to T-cell activation. | 48, 49 |
| KLF13−/− mice have T cells with reduced RANTES expression and enlarged thymi and spleen. | ||
| Increases T-cell survival by decreasing BCL-XL. | 50 | |
| KLF5 | Regulates lineage-specific germline TCRβ expression. | 53 |
| Binds to GC-rich area of the TCR Dβ1 promoter. | ||
| KLF6 | Regulates iNOS promoter activity in Jurkat T cells. | 55 |
| Activated by hypoxia, heat shock, or serum starvation. | ||
| Monocyte/macrophage | ||
| KLF4 | Robustly expressed in PBMCs and in a stage-specific manner during myelopoiesis. | 61 |
| Overexpression in CMPs or HSCs induces exclusive monocyte differentiation. | ||
| PU.1 binds to the KLF4 promoter. | ||
| High expression levels of KLF4 and c-Myc allows for prolonged self-renewal of differentiated macrophages deficient in MafB and c-Maf. | 66 | |
| Promotes macrophage activation by: 1) inhibiting TGF-β1 signaling via competition with Smad3 binding for p300/CBP; and 2) regulating expression of HMGB1, a non-histone DNA-binding nuclear protein that serves as a cytokine mediator. | 60, 68 | |
| KLF4−/− fetal liver transplant chimeric mice have nearly depleted circulating inflammatory macrophages in blood and tissues and reduced numbers of resident macrophages. | 62 | |
| Induced by H2O2 in PBMCs from patients with chronic myeloid leukemia. | 69 | |
| KLF2 | Reduced expression in response to LPS and in patients with coronary artery disease; expression increased by statins. | 70, 71 |
| Overexpression represses proinflammatory genes (eg, COX-2, CD40L, MCP-1). | ||
| Inhibits transcriptional activity of NF-κB and AP-1 by recruitment of P/CAF. | ||
| KLF2+/−/ApoE−/− mice develop increased atherosclerosis with increased macrophage lipid uptake and aP2 expression. | 72 | |
| KLF1 | Expressed in macrophages. | 73 |
| Regulates transcription of IL-12p40. | ||
| KLF3 | Expressed in several leukocyte subsets. | 74 |
| KLF3−/− mice develop a myeloproliferative disorder. | ||
| Granulocytes | ||
| KLF4 | Overexpression in CMPs or promyelocytic HL-60 cells inhibits granulocyte differentiation and promotes monocyte differentiation. | 61, 62 |
| KLF4−/− CMPs showed increased granulocyte differentiation and reduced monocyte differentiation in clonogenic assays | 61 | |
| B cells | ||
| KLF4 | Expressed at low levels in pro-B cells; expression increased as cells matured from pre-B cells to mature B cells. Higher expression in naïve mature B cells compared with memory B cells. | 80, 82–83 |
| Regulates cyclin D2. | 82 | |
| FOXO transcription factors target KLF4 promoter in response to BCR activation and PI3K signaling. | 83 | |
| B cell–specific KLF4−/− mice showed either: | ||
| (1) Modest decrease in pre-B cells in bone marrow and mature B cells in spleen; and (2) no differences in B cell development, function, or activation. | 82 | |
| Expressed at low levels in human B cell lymphomas | 83 | |
| Overexpression blocks transformation of pre-B cell by BCR-ABL and depletes leukemic pre-B cells in vivo. | 84 | |
| Imatinib and KLF4 additively induce apoptosis in BCR-ABL transformed pro/pre-B cells. | ||
| KLF9 | Expressed higher in naïve B cells than in memory B cells. | 80 |
| Overexpression reduces B cell proliferation in memory B cells and induces the naïve B cell phenotype. | ||
| KLF2 | Expressed strongly after pre-BCR activation and in resting pre-B cells. | |
| Overexpression increases survival of anti-IgM and anti-CD40 stimulated memory B cells. | 81 | |
| Highly expressed in blood antibody-secreting cells (ASCs) along with S1P1, which can effect IgG plasma cell homing. | 86 |
| Cell type/factor . | Function/observation . | References . |
|---|---|---|
| T cells | ||
| KLF2 | Expressed in single-positive CD4+ and CD8+ T cells, induced by statins and rapamycin, and rapidly extinguished after T-cell activation via the PI3K/AKT signaling pathway. | 24, 30, 33, 34 |
| Regulates T-cell trafficking by targeting S1P1, CD62L, β7-integrin, and chemokine receptors through both autonomous and nonautonomous mechanisms. | 27, 31, 33, 35–36 | |
| Overexpression in CD8+ effector T cells mimics statins' anti-inflammatory effects and ameliorates CD8+ T cell–mediated myocarditis. | 30 | |
| KLF4 | Expressed in CD8+ T cells where it maintains T-cell quiescence downstream of Ets transcription factor ELF. | 37 |
| Regulates expression of p21 in CD8+ T cells. | ||
| KLF4 promoter is densely methylated in PBMCs from patients with adult T-cell leukemia (ATL) compared with healthy controls. | 42 | |
| Overexpression prevents ATL cell proliferation and induces apoptosis. | ||
| KLF10 | Expressed highly in T regulatory cells than CD4+CD25− T cells. | 45, 46 |
| Induced in response to TGF-β1 and the Itch ubiquitin ligase. | ||
| Targets both TGF-β1 and Foxp3 promoters to promote T reg cell differentiation as part of a positive feedback loop. | 45 | |
| Promotes T reg cell suppressor function independent of Foxp3 by increasing the expression of TGF-β1. | ||
| Inhibits Th1 and Th2 differentiation pathways. | ||
| Adoptive transfer of KLF10−/− T cells accelerates atherosclerosis in ApoE−/− scid/scid mice. | ||
| KLF10−/− 'TGF-β1 in vitro converted T regs fail to suppress airway inflammation. | 46 | |
| Genetic variant in KLF10 3′-UTR associated with type 2 diabetes. | 47 | |
| KLF13 | Expressed in response to T-cell activation. | 48, 49 |
| KLF13−/− mice have T cells with reduced RANTES expression and enlarged thymi and spleen. | ||
| Increases T-cell survival by decreasing BCL-XL. | 50 | |
| KLF5 | Regulates lineage-specific germline TCRβ expression. | 53 |
| Binds to GC-rich area of the TCR Dβ1 promoter. | ||
| KLF6 | Regulates iNOS promoter activity in Jurkat T cells. | 55 |
| Activated by hypoxia, heat shock, or serum starvation. | ||
| Monocyte/macrophage | ||
| KLF4 | Robustly expressed in PBMCs and in a stage-specific manner during myelopoiesis. | 61 |
| Overexpression in CMPs or HSCs induces exclusive monocyte differentiation. | ||
| PU.1 binds to the KLF4 promoter. | ||
| High expression levels of KLF4 and c-Myc allows for prolonged self-renewal of differentiated macrophages deficient in MafB and c-Maf. | 66 | |
| Promotes macrophage activation by: 1) inhibiting TGF-β1 signaling via competition with Smad3 binding for p300/CBP; and 2) regulating expression of HMGB1, a non-histone DNA-binding nuclear protein that serves as a cytokine mediator. | 60, 68 | |
| KLF4−/− fetal liver transplant chimeric mice have nearly depleted circulating inflammatory macrophages in blood and tissues and reduced numbers of resident macrophages. | 62 | |
| Induced by H2O2 in PBMCs from patients with chronic myeloid leukemia. | 69 | |
| KLF2 | Reduced expression in response to LPS and in patients with coronary artery disease; expression increased by statins. | 70, 71 |
| Overexpression represses proinflammatory genes (eg, COX-2, CD40L, MCP-1). | ||
| Inhibits transcriptional activity of NF-κB and AP-1 by recruitment of P/CAF. | ||
| KLF2+/−/ApoE−/− mice develop increased atherosclerosis with increased macrophage lipid uptake and aP2 expression. | 72 | |
| KLF1 | Expressed in macrophages. | 73 |
| Regulates transcription of IL-12p40. | ||
| KLF3 | Expressed in several leukocyte subsets. | 74 |
| KLF3−/− mice develop a myeloproliferative disorder. | ||
| Granulocytes | ||
| KLF4 | Overexpression in CMPs or promyelocytic HL-60 cells inhibits granulocyte differentiation and promotes monocyte differentiation. | 61, 62 |
| KLF4−/− CMPs showed increased granulocyte differentiation and reduced monocyte differentiation in clonogenic assays | 61 | |
| B cells | ||
| KLF4 | Expressed at low levels in pro-B cells; expression increased as cells matured from pre-B cells to mature B cells. Higher expression in naïve mature B cells compared with memory B cells. | 80, 82–83 |
| Regulates cyclin D2. | 82 | |
| FOXO transcription factors target KLF4 promoter in response to BCR activation and PI3K signaling. | 83 | |
| B cell–specific KLF4−/− mice showed either: | ||
| (1) Modest decrease in pre-B cells in bone marrow and mature B cells in spleen; and (2) no differences in B cell development, function, or activation. | 82 | |
| Expressed at low levels in human B cell lymphomas | 83 | |
| Overexpression blocks transformation of pre-B cell by BCR-ABL and depletes leukemic pre-B cells in vivo. | 84 | |
| Imatinib and KLF4 additively induce apoptosis in BCR-ABL transformed pro/pre-B cells. | ||
| KLF9 | Expressed higher in naïve B cells than in memory B cells. | 80 |
| Overexpression reduces B cell proliferation in memory B cells and induces the naïve B cell phenotype. | ||
| KLF2 | Expressed strongly after pre-BCR activation and in resting pre-B cells. | |
| Overexpression increases survival of anti-IgM and anti-CD40 stimulated memory B cells. | 81 | |
| Highly expressed in blood antibody-secreting cells (ASCs) along with S1P1, which can effect IgG plasma cell homing. | 86 |