Brigl, M. et al. Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J. Exp. Med. 208, 1163-1177

Department of Pathology, Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 06/2011; 208(6):1163-77. DOI: 10.1084/jem.20102555
Source: PubMed


Invariant natural killer T cells (iNKT cells) are critical for host defense against a variety of microbial pathogens. However, the central question of how iNKT cells are activated by microbes has not been fully explained. The example of adaptive MHC-restricted T cells, studies using synthetic pharmacological α-galactosylceramides, and the recent discovery of microbial iNKT cell ligands have all suggested that recognition of foreign lipid antigens is the main driver for iNKT cell activation during infection. However, when we compared the role of microbial antigens versus innate cytokine-driven mechanisms, we found that iNKT cell interferon-γ production after in vitro stimulation or infection with diverse bacteria overwhelmingly depended on toll-like receptor-driven IL-12. Importantly, activation of iNKT cells in vivo during infection with Sphingomonas yanoikuyae or Streptococcus pneumoniae, pathogens which are known to express iNKT cell antigens and which require iNKT cells for effective protection, also predominantly depended on IL-12. Constitutive expression of high levels of IL-12 receptor by iNKT cells enabled instant IL-12-induced STAT4 activation, demonstrating that among T cells, iNKT cells are uniquely equipped for immediate, cytokine-driven activation. These findings reveal that innate and cytokine-driven signals, rather than cognate microbial antigen, dominate in iNKT cell activation during microbial infections.

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Available from: Fong-Fu Hsu, Oct 01, 2015
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    • "In contrast to the mDCs, pDCs lack the expression of CD1d, which is an important molecule for crosstalk with iNKT cells (105). Nonetheless, over the past few years the ability of iNKT cell to “sense” subtle changes within their microenvironment in a CD1d-independent mechanism, uncovered that cytokines released by pDCs are essential (106, 107). Indeed, CpG activated pDCs upregulate activation markers on iNKT cells via TNF-α and IFN-α release, and selectively enhance double-negative iNKT cell survival but not that of other NKT cell populations (104). "
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    ABSTRACT: Plasmacytoid dendritic cells (pDCs) are a specific subset of naturally occurring dendritic cells, that secrete large amounts of Type I interferon and play an important role in the immune response against viral infection. Several studies have highlighted that they are also effective antigen presenting cells, making them an interesting target for immunotherapy against cancer. However, the modes of action of pDCs are not restricted to antigen presentation and IFN secretion alone. In this review we will highlight a selection of cell surface proteins expressed by human pDCs that may facilitate communication with other immune cells, and we will discuss the implications of these molecules for pDC-driven immune responses.
    Frontiers in Immunology 11/2013; 4:372. DOI:10.3389/fimmu.2013.00372
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    • "iNKT cells are actively recruited to infection sites, where they respond to cytokines and interact with CD1d+ mDC [5]. In response to stimuli, iNKT cells can release large amounts of regulatory cytokines and are believed to play a pivotal role in the determination of innate and adaptive immune system responses [6]. iNKT cells can be subdivided into three subsets: CD4+, CD8+ and CD4−/CD8− double negative (DN). "
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    ABSTRACT: A significant barrier to effective immune clearance of cancer is loss of antitumor cytotoxic T cell activity. Antibodies to block pro-apoptotic/downmodulatory signals to T cells are currently being tested. Because invariant natural killer T cells (iNKT) can regulate the balance of Th1/Th2 cellular immune responses, we characterized the frequencies of circulating iNKT cell subsets in 21 patients with melanoma who received the anti-CTLA4 monoclonal antibody tremelimumab alone and 8 patients who received the antibody in combination with MART-126-35 peptide-pulsed dendritic cells (MART-1/DC). Blood T cell phenotypes and functionality were characterized by flow cytometry before and after treatment. iNKT cells exhibited the central memory phenotype and showed polyfunctional cytokine production. In the combination treatment group, high frequencies of pro-inflammatory Th1 iNKT CD8(+) cells correlated with positive clinical responses. These results indicate that iNKT cells play a critical role in regulating effective antitumor T cell activity.
    PLoS ONE 10/2013; 8(10):e76829. DOI:10.1371/journal.pone.0076829 · 3.23 Impact Factor
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    • "Many PLZF-regulated genes from our analysis were differentially expressed between iNKT and CD4+ thymocytes (Figure 1C), consistent with our gene set representing the NKT molecular program. Since Id2 (Monticelli et al., 2009), c-Maf (Kim et al., 1999), as well as ICOS (Akbari et al., 2008; Chung et al., 2008; Watanabe et al., 2010), IL12R (Brigl et al., 2003, 2011), and IL18R (Nagarajan and Kronenberg, 2007; Velazquez et al., 2008) signaling pathways had previously been implicated in NKT cell development, homeostasis and/or function, we proceeded to validate these targets in iNKT and γδNKT cells from wt and PLZF-deficient mice that did not express TCR transgenes. "
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    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
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