Role of Kruppel-like factors in leukocyte development, function, and disease

Abstract

The Krüppel-like transcription factor (KLF) family participates in diverse aspects of cellular growth, development, differentiation, and activation. Recently, several groups have identified new connections between the function of these factors and leukocyte responses in health and disease. Gene targeting of individual KLFs in mice has uncovered novel and unexpected physiologic roles among myeloid and lymphocyte cell lineage maturation, particularly in the bone marrow niche and blood. In addition, several KLF family members are downstream targets of stimuli and signaling pathways critical to T-cell trafficking, T regulatory cell differentiation or suppressor function, monocyte/macrophage activation or renewal, and B memory cell maturation or activation. Indeed, KLFs have been implicated in subtypes of leukemia, lymphoma, autoimmunity, and in acute and chronic inflammatory disease states, such as atherosclerosis, diabetes, and airway inflammation, raising the possibility that KLFs and their upstream signals are of therapeutic interest. This review focuses on the relevant literature of Krüppel-like factors in leukocyte biology and their implications in clinical settings.

Figure 1

Schematic representation of trans-acting domains and molecular mechanisms of leukocyte-associated KLFs. (A) Comparison of KLF subdomains for: KLF1, KLF2,^, KLF3,^, KLF4, KLF5,^, KLF6, KLF9,^– KLF10,^, and KLF13.^, The “zinc fingers” are represented by red boxes. The trans-activation domains are indicated by orange boxes, whereas the trans-repression domains are indicated by blue boxes. (B) Role of KLFs in regulating signaling pathways and transcriptional targets that affect leukocytes in health and disease. On activation by stimuli, such as the TCR, BCR, cytokines/growth factors, drugs (statins, rapamycin), or environmental pollutants (dioxin), the upstream cytoplasmic (eg, AKT/PI3K) or nuclear (eg, PU.1 or FOXO1) effector proteins transduce signals that can activate or inhibit nuclear KLFs. KLFs, in turn, induce or repress target genes (alone or in association with coactivators or corepressors) that affect leukocyte cell growth and differentiation, survival, activation, or homing and recruitment, ultimately affecting various disease states.

Figure 2

Role of KLFs in T-cell development, activation, and trafficking. In response to activation of TCR signaling, KLF2 expression is reduced, whereas the immunomodulatory drugs “statins” and rapamycin increase KLF2 expression. KLF2 is required for: (1) maintaining the quiescent state of single-positive CD4⁺ or CD8⁺ T cells; (2) induction of T-cell trafficking markers S1P1, CD62L, β7-integrin on thymic CD4⁺ T cells to allow for egress into peripheral lymphoid tissues; and (3) expression of chemokine receptors, such as CCR3, CCR5, and CXCR3, by autonomously or nonautonomously regulating levels of IL-4 in CD8⁺ T cells. The Ets transcription factor ELF activates KLF4 expression to negatively regulate naive CD8⁺ T-cell proliferation and induces KLF2 to promote T-cell homing. In response to TGF-β1, KLF10 expression is induced and promotes Treg cell differentiation by targeting both TGF-β1 and Foxp3 as part of a positive feedback loop; in contrast, KLF10 inhibits Th1 and Th2-mediated pathways. KLF10 also promotes Treg cell suppressor function independent of Foxp3 by increasing the expression of TGF-β1 in Tregs.

Figure 3

Role of KLFs in myeloid development, renewal, and activation. (A) KLF4 and PU.1 are expressed in a stage-specific pattern during myelopoiesis (adapted with permission; see Feinberg et al). (B-F) Overexpression of KLF4 in CMPs or HSCs promotes exclusive monocyte differentiation, whereas PU.1 promotes both monocytic and granulocytic differentiation (adapted with permission; see Feinberg et al). (G) Schematic overview of KLFs in monocyte biology. KLF4 is a downstream target gene of PU.1 that promotes monocyte differentiation from hematopoietic stem cell progenitors. High expression levels of KLF4 and c-Myc enable differentiated monocytes/macrophages capable of self-renewal, an effect regulated by MafB and c-Maf and potentially mediated by their respective downstream targets, PU.1 and Ets1/2. Statins induce KLF2, which can repress genes involved in macrophage activation. KLF4 promotes the development of inflammatory monocytes (Ly-6C⁺, CD62L⁺, CCR2⁺) in blood and tissues and, to a lesser extent, resident macrophages in tissues (Ly6C⁻, CD62L⁻, CCR2⁻).

Figure 4

Role of KLFs in B-cell differentiation and activation. In response to activation of the BCR, FOXO transcription factors target KLF4 which, on overexpression, inhibits B-cell proliferation and promotes G₁ cell-growth arrest. Conversely, B cell–specific, KLF4-deficient mice have displayed modest differentiation defects of pre-B cells in bone marrow and mature B cells in spleen; however, no differences were observed in these types of B cells using a similar conditional knockout model. KLF4 or KLF9 overexpression reduces the number of proliferating memory B cells, and their behavior resembles that of naive B cells. In contrast, KLF2 increases the survival of anti-IgM and anti–CD40-stimulated memory B cells.