PRDM1/Blimp-1 Controls Effector Cytokine Production in Human NK Cells
ABSTRACT 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.
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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 · 12.64 Impact Factor
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ABSTRACT: Natural killer (NK) cells are an innate lymphoid cell lineage characterized by their capacity to provide rapid effector functions, including cytokine production and cytotoxicity. Here, we identify the Ikaros family member, Aiolos, as a regulator of NK-cell maturation. Aiolos expression is initiated at the point of lineage commitment and maintained throughout NK-cell ontogeny. Analysis of cell surface markers representative of distinct stages of peripheral NK-cell maturation revealed that Aiolos was required for the maturation in the spleen of CD11bhighCD27− NK cells. The differentiation block was intrinsic to the NK-cell lineage and resembled that found in mice lacking either T-bet or Blimp1; however, genetic analysis revealed that Aiolos acted independently of all other known regulators of NK-cell differentiation. NK cells lacking Aiolos were strongly hyper-reactive to a variety of NK-cell-mediated tumor models, yet impaired in controlling viral infection, suggesting a regulatory function for CD27− NK cells in balancing these two arms of the immune response. These data place Aiolos in the emerging gene regulatory network controlling NK-cell maturation and function.The EMBO Journal 10/2014; DOI:10.15252/embj.201487900 · 10.75 Impact Factor
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ABSTRACT: The majority of T lymphocytes, sometimes referred to as as mainstream or conventional T cells, are characterized by a diverse T cell antigen receptor (TCR) repertoire. They require antigen priming in order to become memory cells capable of mounting a rapid effector response. It has become established, however, that there are several distinct T cell lineages that exhibit a memory phenotype in the absence of antigen priming, even as they differentiate in the thymus. These lymphocytes typically express a markedly restricted TCR repertoire and their rapid response kinetics has led to their being described as innate-like T cells. In addition, several of these subsets typically express surface markers commonly found on natural killer cells, which has led to the moniker natural killer T cells (NKT cells). This review will describe our current understanding of the unique ways whereby transcription factors control the development and function of an abundant and widely studied lineage of NKT cells that recognizes glycolipid antigens.Current topics in microbiology and immunology 05/2014; DOI:10.1007/82_2014_375 · 3.47 Impact Factor