Kruppel-Like Factor 2 Regulates Trafficking and Homeostasis of T Cells

Center for Immunology and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55414, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2010; 184(11):6060-6. DOI: 10.4049/jimmunol.1000511
Source: PubMed


gammadelta T cells are generated in the thymus and traffic to secondary lymphoid organs and epithelial surfaces, where they regulate immune responses. alphabeta T cells require sphingosine 1-phosphate receptor type 1 (S1P(1)) and CD62L for thymic emigration and circulation through secondary lymphoid organs. Both of these genes are regulated by the transcription factor Krüppel-like factor 2 (KLF2) in conventional alphabeta T cells. It is unclear if gammadelta T cells use similar mechanisms. In this study, we show that thymic gammadelta T cells express S1P(1) and that it is regulated by KLF2. Furthermore, KLF2 and S1P(1)-deficient gammadelta T cells accumulate in the thymus and fail to populate the secondary lymphoid organs or gut, in contrast to the expectation from published work. Interestingly, KLF2 but not S1P(1) deficiency led to the expansion of a usually rare population of CD4(+) promyelocytic leukemia zinc finger(+) "gammadelta NKT" cells. Thus, KLF2 is critically important for the homeostasis and trafficking of gammadelta T cells.

Download full-text


Available from: Oludare Odumade,
20 Reads
  • Source
    • "In conditions of chronic stress, including ageing, the zinc release by MT is limited, leading to low intracellular zinc bioavailability and subsequent reduced innate immunity (Mocchegiani et al., 2006a,b). Additionally, a zinc finger motif [Krü ppel-like factor 2 (Kfl2] plays an important role in the immune response of gdNKT cells (Odumade et al., 2010). In zinc deficiency, gdNKT cell cytotoxicity and Kfl2 activity are impaired (Mocchegiani et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent longitudinal studies in dietary daily intake in human centenarians have shown that a satisfactory content of some micronutrients within the cells maintain several immune functions, a low grade of inflammation and preserve antioxidant activity. Micronutrients (zinc, copper, selenium) play a pivotal role in maintaining and reinforcing the performances of the immune and antioxidant systems as well as in affecting the complex network of the genes (nutrigenomic) with anti- and pro-inflammatory tasks. Genes of pro- and anti-inflammatory cytokines and some key regulators of trace elements homeostasis, such as Metallothioneins (MT), are involved in the susceptibility to major geriatric disease/disorders. Moreover, the genetic inter-individual variability may affect the nutrients' absorption (nutrigenetic) with altered effects on inflammatory/immune response and antioxidant activity. The interaction between genetic factors and micronutrients (nutrigenomic and nutrigenetic approaches) may influence ageing and longevity because the micronutrients may become also toxic. This review reports the micronutrient-gene interactions in ageing and their impact on the healthy state with a focus on the method of protein-metal speciation analysis. The association between micronutrient-gene interactions and the protein-metal speciation analysis can give a complete picture for a personalized nutrient supplementation or chelation in order to reach healthy ageing and longevity.
    Mechanisms of ageing and development 01/2014; 136-137. DOI:10.1016/j.mad.2013.12.007 · 3.40 Impact Factor
  • Source
    • "PLZF expression by NKT and NKT-like cells also has a far-reaching influence on other immune cells. Mice deficient in Itk (Felices et al., 2009; Qi et al., 2009), Id3 (Lauritsen et al., 2009; Ueda-Hayakawa et al., 2009; Verykokakis et al., 2010a), and KLF2 (Odumade et al., 2010), as well as mice with mutated SLP-76 (Alonzo et al., 2009) and mice transgenic for Dok-1 (Besin et al., 2012) have increased numbers of PLZF-expressing cells – a phenomenon yet to be explained. IL-4 secretion by these PLZF-expressing cells leads to acquisition of innate-like features by CD8 T cells (Verykokakis et al., 2010b; Weinreich et al., 2010; Gordon et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NKT) T cells exhibit tissue distribution, surface phenotype, and functional responses that are strikingly different from those of conventional T cells. The transcription factor PLZF is responsible for most of these properties, as its ectopic expression in conventional T cells is sufficient to confer to them an NKT-like phenotype. The molecular program downstream of PLZF, however, is largely unexplored. Here we report that PLZF regulates the expression of a surprisingly small set of genes, many with known immune functions. This includes several established components of the NKT cell developmental program. Expression of the transcriptional regulators Id2, previously shown to be required for iNKT cell survival in the liver and c-Maf, which shapes the NKT cytokine profile, was compromised in PLZF-deficient cells. Ectopic expression of c-Maf complemented the cells' defect in producing IL-4 and IL-10. PLZF also induced a program of cell surface receptors which shape the NKT cell's response to external stimuli, including the costimulatory receptor ICOS and the cytokine receptors IL12rb1 and IL18r1. As an ensemble, the known functions of the molecules whose expression is affected by PLZF explain many defects observed in PLZF(-/-) NKT cells.
    Frontiers in Immunology 12/2012; 3:374. DOI:10.3389/fimmu.2012.00374
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CD8(+) T cells are selected via low-affinity interaction with MHC class I molecules on thymic epithelial cells (TECs). However, compromised T cell receptor signaling was proposed to force CD8(+) T cell selection on hematopoietic cells through a SLAM-associated protein (SAP)-dependent mechanism similar to NKT cells. The outcome is an unconventional CD8(+) T cell with phenotypic and functional characteristics of innate lymphocytes. Here we showed that Id3(-/-) CD8(+) T cells had an innate-like phenotype and required SAP for their development. However, like conventional CD8(+) T cells, Id3(-/-) CD8(+) thymocytes were selected on TECs. The requirement for SAP and the innate-like phenotype was not intrinsic to Id3(-/-) CD8(+) thymocytes. Rather, an expanded population of NKT-like cells induced the innate phenotype on CD8(+) T cells through production of interleukin-4. Our findings reveal that accumulation of NKT-like cells promotes conventional CD8(+) thymocytes to acquire innate lymphocyte characteristics.
    Immunity 08/2010; 33(2):203-15. DOI:10.1016/j.immuni.2010.07.013 · 21.56 Impact Factor
Show more