PRDM1/Blimp-1 Controls Effector Cytokine Production in Human NK Cells

H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL 33612, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(10):6058-67. DOI: 10.4049/jimmunol.1001682
Source: PubMed


NK cells are major effectors of the innate immune response through cytolysis and bridge to the adaptive immune response through cytokine release. The mediators of activation are well studied; however, little is known about the mechanisms that restrain activation. In this report, we demonstrate that the transcriptional repressor PRDM1 (also known as Blimp-1 or PRDI-BF1) is a critical negative regulator of NK function. Three distinct PRDM1 isoforms are selectively induced in the CD56(dim) NK population in response to activation. PRDM1 coordinately suppresses the release of IFN-γ, TNF-α, and TNF-β through direct binding to multiple conserved regulatory regions. Ablation of PRDM1 expression leads to enhanced production of IFN-γ and TNF-α but does not alter cytotoxicity, whereas overexpression blocks cytokine production. PRDM1 response elements are defined at the IFNG and TNF loci. Collectively, these data demonstrate a key role for PRDM1 in the negative regulation of NK activation and position PRDM1 as a common regulator of the adaptive and innate immune response.

11 Reads
  • Source
    • "It was later determined to program the terminal differentiation of B cells into immunoglobulin-secreting plasma cells (Turner et al. 1994). PRDM1 has also been detected in a subset of diffuse large B cell lymphomas (Pasqualucci et al. 2006), macrophages (Chang et al. 2000) and natural killer cells (Smith et al. 2010). In addition, recent studies have implied that PRDM1 functions in regulating T cell activation and homeostasis (Martins et al. 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: PRDM1 (PR domain containing 1) is a transcriptional repressor that has been identified in various species and is crucial for cell growth, differentiation and development. However, the expression pattern and role of PRDM1 in development has not been sufficiently established in birds. We therefore investigate the spatio-temporal expression of PRDM1 in various tissues, especially in the germline, during chicken development, providing the basis for functional study. Our results show that prdm1 mRNA was expressed in blastodermal cells (BCs) at stage X and in various tissues including the liver, skin, lung, kidney, eye, bursa of fabricius, spleen, proventriculus, gizzard, intestine, testis, ovary, tongue, feathers and thymus but was not or was only sparcely present in the heart, brain and skeletal muscle. The level of prdm1 mRNA was highest in the BCs among all tissues tested and significantly changed during development in many tissues, such as the blastoderm, bursa of fabricius, spleen, feathers and germline. Furthermore, the expression of the PRDM1 protein generally paralleled the mRNA results, except for in the gizzard. Immunohistochemistry also revealed that PRDM1 was localized in the smooth muscle. In addition, during germline development, PRDM1 was found to be continuously expressed in the presumptive primordial germ cells (PGCs) at stage X, the circulating PGCs in blood and the germ cells in the gonads from embryonic day 6 to adult in both males and females. The expression pattern of PRDM1 in chicken thus suggests that this protein plays an important role during chicken development, such as in BC differentiation, feather formation and germ cell specification. Electronic supplementary material The online version of this article (doi:10.1007/s00441-014-1804-1) contains supplementary material, which is available to authorized users.
    Cell and Tissue Research 04/2014; 356(2). DOI:10.1007/s00441-014-1804-1 · 3.57 Impact Factor
  • Source
    • "Then, we investigated the protein levels of Blimp-1. In this regard, three distinct Blimp-1 isoforms have been described: the active full-length α isoform (Blimp-1α), the β isoform (Blimp-1β) with a damped activity and the intermediate-sized Blimp-1αΔ isoform, reported to interfere negatively with Blimp-1α [33,34]. Notably, only Blimp-1α isoform was clearly detected in extracts derived from IFN-α DC at day 3 of differentiation (Figure 2B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type I interferon (IFN-I) have emerged as crucial mediators of cellular signals controlling DC differentiation and function. Human DC differentiated from monocytes in the presence of IFN-α (IFN-α DC) show a partially mature phenotype and a special capability of stimulating CD4+ T cell and cross-priming CD8+ T cells. Likewise, plasmacytoid DC (pDC) are blood DC highly specialized in the production of IFN-α in response to viruses and other danger signals, whose functional features may be shaped by IFN-I. Here, we investigated the molecular mechanisms stimulated by IFN-α in driving human monocyte-derived DC differentiation and performed parallel studies on peripheral unstimulated and IFN-α-treated pDC. A specific miRNA signature was induced in IFN-α DC and selected miRNAs, among which miR-23a and miR-125b, proved to be negatively associated with up-modulation of Blimp-1 occurring during IFN-α-driven DC differentiation. Of note, monocyte-derived IFN-α DC and in vitro IFN-α-treated pDC shared a restricted pattern of miRNAs regulating Blimp-1 expression as well as some similar phenotypic, molecular and functional hallmarks, supporting the existence of a potential relationship between these DC populations. On the whole, these data uncover a new role of Blimp-1 in human DC differentiation driven by IFN-α and identify Blimp-1 as an IFN-α-mediated key regulator potentially accounting for shared functional features between IFN-α DC and pDC.
    PLoS ONE 08/2013; 8(8):e72833. DOI:10.1371/journal.pone.0072833 · 3.23 Impact Factor
  • Source
    • "To examine temporally and spatially restricted Blimp1 expression patterns by trophoblast cell subpopulations in the developing placenta, we performed in situ hybridization and immunostaining experiments. Recent evidence suggests that Blimp1 regulates NK cell maturation and effector functions (Smith et al. 2010; Kallies et al. 2011). Additionally, uterine NK cells may be required for remodeling of maternal blood vessels during placentation (Adamson et al. 2002; Moffett and Loke 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Developmental arrest of Blimp1/Prdm1 mutant embryos at around embryonic day 10.5 (E10.5) has been attributed to placental disturbances. Here we investigate Blimp1/Prdm1 requirements in the trophoblast cell lineage. Loss of function disrupts specification of the invasive spiral artery-associated trophoblast giant cells (SpA-TGCs) surrounding maternal blood vessels and severely compromises the ability of the spongiotrophoblast layer to expand appropriately, secondarily causing collapse of the underlying labyrinth layer. Additionally, we identify a population of proliferating Blimp1(+) diploid cells present within the spongiotrophoblast layer. Lineage tracing experiments exploiting a novel Prdm1.Cre-LacZ allele demonstrate that these Blimp1(+) cells give rise to the mature SpA-TGCs, canal TGCs, and glycogen trophoblasts. In sum, the transcriptional repressor Blimp1/Prdm1 is required for terminal differentiation of SpA-TGCs and defines a lineage-restricted progenitor cell population contributing to placental growth and morphogenesis.
    Genes & development 09/2012; 26(18):2063-74. DOI:10.1101/gad.199828.112 · 10.80 Impact Factor
Show more