A role for interleukin-12/23 in the maturation of human natural killer and CD56+ T cells in vivo

Guia, Sophie; Cognet, Céline; Beaucoudrey, Ludovic de; Tessmer, Marlowe S.; Jouanguy, Emmanuelle; Berger, Claire; Filipe-Santos, Orchidée; Feinberg, Jacqueline; Camcioğlu, Yıldız; Levy, Jacob; Jumaah, Suliman Al; Al-Hajjar, Sami; Stéphan, Jean-Louis; Fieschi, Claire; Abel, Laurent; Brossay, Laurent; Casanova, Jean‐Laurent; Vivier, Éric

doi:10.1182/blood-2007-11-122259

Cited by 57 publications

(51 citation statements)

References 73 publications

(96 reference statements)

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“…IL12RB1 is critical for IL-12-and IL-23-dependent leukocyte responses: CD4 + Th cells of individuals homozygous for nonfunctioning IL12RB1 (i.e., IL12RB1 mut ) alleles exhibit defective Th1 and Th17 polarization (19,20,50), NK cells from IL12RB1 mut individuals are hyporeactive (6), and the frequency of CD56 + T cells in the circulation of IL12RB1 mut individuals is low (6). These combined immunological defects leave IL12RB1 mut individuals more susceptible to infection by mycobacteria, Salmonella, and Candida species, as reported in a recent extensive international study (20).…”

Section: Discussionmentioning

confidence: 99%

“…T he cytokines IL-12 and IL-23 influence numerous aspects of adaptive and innate human immunity, including the differentiation of helper T and NK cell subsets (1)(2)(3)(4)(5)(6), enhancing cytolytic T cell responses (7), promoting B cell production of select Ig isotypes (8), and regulating dendritic cell activity (9). The biological activities of IL-12 and IL-23 are dependent on IL-12Rb1, a type I integral membrane protein that serves as a low-affinity receptor for the p40 subunit of both cytokines (10)(11)(12).…”

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confidence: 99%

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Inflammatory Signals Direct Expression of Human IL12RB1 into Multiple Distinct Isoforms

Ford

Miller

Reeme

et al. 2012

The Journal of Immunology

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IL12RB1 is essential for human resistance to multiple intracellular pathogens, including Mycobacterium tuberculosis. In its absence, the proinflammatory effects of the extracellular cytokines IL-12 and IL-23 fail to occur, and intracellular bacterial growth goes unchecked. Given the recent observation that mouse leukocytes express more than one isoform from il12rb1, we examined whether primary human leukocytes similarly express more than one isoform from IL12RB1. We observed that human leukocytes express as many as 13 distinct isoforms, the relative levels of each being driven by inflammatory stimuli both in vitro and in vivo. Surprisingly, the most abundant isoform present before stimulation is a heretofore uncharacterized intracellular form of the IL-12R (termed “isoform 2”) that presumably has limited contact with extracellular cytokine. After stimulation, primary PBMCs, including the CD4+, CD8+, and CD56+ lineages contained therein, alter the splicing of IL12RB1 RNA to increase the relative abundance of isoform 1, which confers IL-12/IL-23 responsiveness. These data demonstrate both a posttranscriptional mechanism by which cells regulate their IL-12/IL-23 responsiveness, and that leukocytes primarily express IL12RB1 in an intracellular form located away from extracellular cytokine.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inflammatory Signals Direct Expression of Human IL12RB1 into Multiple Distinct Isoforms

Ford

Miller

Reeme

et al. 2012

The Journal of Immunology

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“…As an example, IL12 is crucial for human NK-cell activity [37]. Accordingly, in the absence of costimulatory signals (i.e.…”

Section: Discussionmentioning

confidence: 99%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...

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“…Because only a minor fraction of circulating NK cells is reactive to target cells (tumor cells) in vitro, primary NK cells show insufficient cytotoxicity [14]. Various types of stimulation have thus been reported to enable NK cells to achieve their full effector potential, such as interleukin (IL)-15 produced by dendritic cells (DCs) [15] or macrophages [16], IL-2 [17], IL-12 [18], IL-18 [19] and IL-21 [20]. Currently, the additional cytokines used in the cultivation of NK cells include IL-2, IL-15, and IL-21.…”

Section: Activation Of Nk Cellsmentioning

confidence: 99%

Clinical Applications of Natural Killer Cells

Harada¹,

Teraishi²,

Ishii³

et al. 2017

Natural Killer Cells

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Natural killer (NK) cells are an essential component of the innate immune system, and they play a crucial role in immunity against malignancies. Recent advances in our understanding of NK cell biology have paved the way for new therapeutic strategies based on NK cells for the treatment of various cancers. In this section, we will focus on NK cell immunotherapy, including the enhancement of antibody-dependent cellular cytotoxicity, the manipulation of receptor-mediated activation, inclusion criteria based on killer cell immunoglobulin-like receptor (KIR) ligand mismatches, and adoptive immunotherapy with ex vivo expanded chimeric antigen receptor (CAR)-engineered or engager-modified NK cells. In contrast to T lymphocytes, donor NK cells do not attack any recipient tissues based on allogeneic human leukocyte antigens (HLAs), suggesting that NK-mediated antitumor effects may be achieved without the risk of graft-versus-host disease (GvHD). Despite reports of clinical efficacy, the application of NK cell immunotherapy is limited. Developing strategies for manipulating NK cell products, host factors, and tumor targets are thus current subjects of diligent study. Research into the biology of NK cells has indicated that NK cell immunotherapy has the potential to become the forefront of cancer immunotherapy in the coming years.

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A role for interleukin-12/23 in the maturation of human natural killer and CD56+ T cells in vivo

Cited by 57 publications

References 73 publications

Inflammatory Signals Direct Expression of Human IL12RB1 into Multiple Distinct Isoforms

Inflammatory Signals Direct Expression of Human IL12RB1 into Multiple Distinct Isoforms

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

Clinical Applications of Natural Killer Cells

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