Plasticity of invariant NKT cell regulation of allergic airway disease is dependent on IFN-gamma production.

Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO 80206, USA.
The Journal of Immunology (Impact Factor: 5.52). 07/2010; 185(1):253-62. DOI: 10.4049/jimmunol.0902301
Source: PubMed

ABSTRACT Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA-alpha-galactosylceramide (OVA/alphaGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/alphaGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/alphaGalCer BMDCs into IFN-gamma-deficient (IFN-gamma(-/-)) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-gamma treatment following OVA-BMDC transfer. Further, Jalpha18-deficient recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/alphaGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-gamma(-/-) mice restored the development of these responses in Jalpha18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/alphaGalCer BMDC transfer. iNKT cells from these IFN-gamma(-/-) mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-gamma as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Extracellular adenosine regulates inflammatory responses via the A2A adenosine receptor (A2AR). A2AR-deficiency results in much exaggerated acute hepatitis, indicating non-redundancy of adenosine-A2AR pathway in inhibiting immune activation. To identify a critical target of immunoregulatory effect of extracellular adenosine, we focused on NKT cells, which play an indispensable role in hepatitis. An A2AR agonist abolished NKT-cell-dependent induction of acute hepatitis by Con A or α-galactosylceramide (α-GalCer) in mice, corresponding to downregulation of activation markers and cytokines in NKT cells and of NK-cell co-activation. These results show that A2AR signaling can downregulate NKT-cell activation and suppress NKT-cell-triggered inflammatory responses. Next, we hypothesized that NKT cells might be under physiological control of the adenosine-A2AR pathway. Indeed, both Con A and α-GalCer induced more severe hepatitis in A2AR(-/-) mice than in wild-type controls. Transfer of A2AR(-/-) NKT cells into A2AR-expressing recipients resulted in exaggeration of Con A-induced liver damage, suggesting that NKT cell activation is controlled by endogenous adenosine via A2AR, and this physiological regulatory mechanism of NKT cells is critical in the control of tissue-damaging inflammation. The current study suggests the possibility to manipulate NKT-cell activity in inflammatory disorders through intervention to the adenosine-A2AR pathway. This article is protected by copyright. All rights reserved.
    European Journal of Immunology 01/2014; · 4.97 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: T helper 2 (Th2) cells play crucial roles in the development of allergic asthma, while various distinct cell populations also contribute to the pathogenesis of the disease. Invariant natural killer T (iNKT) cells produce large amounts of cytokines such as IL-4 and IFNγ upon stimulation with a ligand, α-galactosylceramide, and regulate various immune responses. Recently, a critical role of iNKT cells in the mouse model of asthma and also in asthma patients has been reported, while some contradictory results have also been described. Here, we summarize the experimental results in mouse and human systems, and discuss the current understanding of the role of NKT cells in the pathogenesis of asthma, including a possible mechanism by which iNKT cells are activated in asthma patients.
    Current opinion in immunology 12/2010; 22(6):807-13. · 10.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: NKT cells are a heterogeneous subset of specialized, self-reactive T cells, with innate and adaptive immune properties, which allow them to bridge innate and adaptive immunity and profoundly influence autoimmune and malignant disease outcomes. NKT cells mediate these activities through their ability to rapidly express pro- and anti-inflammatory cytokines that influence the type and magnitude of the immune response. Not only do NKT cells regulate the functions of other cell types, but experimental evidence has found NKT cell subsets can modulate the functions of other NKT subsets. Depending on underlying mechanisms, NKT cells can inhibit or exacerbate autoimmunity and malignancy, making them potential targets for disease intervention. NKT cells can respond to foreign and endogenous antigenic glycolipid signals that are expressed during pathogenic invasion or ongoing inflammation, respectively, allowing them to rapidly react to and influence a broad array of diseases. In this article we review the unique development and activation pathways of NKT cells and focus on how these attributes augment or exacerbate autoimmune disorders and malignancy. We also examine the growing evidence that NKT cells are involved in liver inflammatory conditions that can contribute to the development of malignancy.
    Immunotherapy 10/2011; 3(10):1167-84. · 2.39 Impact Factor

Full-text (2 Sources)

Available from
Jun 1, 2014