The biology of NKT cells

Howard Hughes Medical Institute, Committee on Immunology, Department of Pathology University of Chicago, Chicago, Illinois 60637, USA.
Annual Review of Immunology (Impact Factor: 39.33). 02/2007; 25(1):297-336. DOI: 10.1146/annurev.immunol.25.022106.141711
Source: PubMed


Recognized more than a decade ago, NKT cells differentiate from mainstream thymic precursors through instructive signals emanating during TCR engagement by CD1d-expressing cortical thymocytes. Their semi-invariant alphabeta TCRs recognize isoglobotrihexosylceramide, a mammalian glycosphingolipid, as well as microbial alpha-glycuronylceramides found in the cell wall of Gram-negative, lipopolysaccharide-negative bacteria. This dual recognition of self and microbial ligands underlies innate-like antimicrobial functions mediated by CD40L induction and massive Th1 and Th2 cytokine and chemokine release. Through reciprocal activation of NKT cells and dendritic cells, synthetic NKT ligands constitute promising new vaccine adjuvants. NKT cells also regulate a range of immunopathological conditions, but the mechanisms and the ligands involved remain unknown. NKT cell biology has emerged as a new field of research at the frontier between innate and adaptive immunity, providing a powerful model to study fundamental aspects of the cell and structural biology of glycolipid trafficking, processing, and recognition.

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    • "Type II nonclassical NKT cells are unreactive to a-GalCer and have TCR a chain diversity but are CD1d dependent. NKT-like (or type III) cells are CD1d independent, unresponsive to a-GalCer, and possess diverse TCR a chains (Bendelac et al., 2007). Following TCR engagement by glycolipid presented by CD1d, iNKT cells undergo proliferative expansion and secrete cytokines (Kawano et al., 1997; Crowe et al., 2003; Parekh et al., 2005; Godfrey et al., 2010). "
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    ABSTRACT: MAPK signaling is important for T lymphocyte development, homeostasis, and effector responses. To better understand the role of Mekk1 (encoded by Map3k1) in T cells, we conditionally deleted Map3k1 in Lck Cre/+ Map3k1 f/f mice, and these display larger iNKT cell populations within the liver, spleen, and bone marrow. Mekk1 signaling controls splenic and liver iNKT cell expansion in response to glycolipid antigen. Lck Cre/+ Map3k1 f/f mice have enhanced liver damage in response to glycolipid antigen. Mekk1 regulates Jnk activation in iNKT cells and binds and transfers Lys63-linked poly-ubiquitin onto Carma1. Map3k1 is critical for the regulation of p27Kip1 (encoded by Cdkn1b). Suddason et al. use a T-cell-specific deletion of Map3k1 to show that Mekk1 regulates TCR-dependent Jnk activation and Cdkn1b expression to drive proliferation in response to antigen.
    Full-text · Article · Jan 2016 · Cell Reports
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    • "aGalCer contains an aanomeric linkage of a galactose sugar to the ceramide lipid and this a-linkage is crucial for its stimulatory capacity (Kawano et al. 1997; Morita et al. 1995). In contrast, the overwhelming majority of mammalian glycolipids utilize a b-linkage of the sugar (Bendelac et al. 2007; Brennan et al. 2013; Kronenberg 2005; Rossjohn et al. 2012), although recently a-linked iNKT cell antigens of mammalian origin were also discovered (Kain et al. 2014). aGalCer binds to CD1d via its two lipid chains, exposing the a-linked sugar group for recognition by the invariant TCR. "
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    ABSTRACT: Invariant natural killer T (iNKT) cells are a unique subset of innate T cells that share features with innate NK cells and adaptive memory T cells. The first iNKT cell antigen described was found 1993 in a marine sponge and it took over 10 years for other, bacterial antigens to be described. Given the paucity of known bacterial iNKT cell antigens, it appeared as if iNKT cells play a very specialist role in the protection against few, rare and unusual pathogenic bacteria. However, in the last few years several publications painted a very different picture, suggesting that antigens for iNKT cells are found almost ubiquitous in the environment. These environmental iNKT cell antigens can shape the distribution, phenotype and function of iNKT cells. Here, these recent findings will be reviewed and their implications for the field will be outlined.
    Full-text · Article · Dec 2015 · Archivum Immunologiae et Therapiae Experimentalis
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    • "Natural killer T (NKT) cells are innate-like lymphocytes typified by coexpression of receptors characteristic of natural killer and conventional T cells [1]. As such, murine NKT cells generally bear Ly49 receptors, NKG2 family of receptors, CD94, and NK1.1 (the latter only being expressed in specific strains, including the commonly used C57BL/6). "
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    ABSTRACT: Natural killer T (NKT) cells are innate-like lymphocytes that were first described in the late 1980s. Since their initial description, numerous studies have collectively shed light on their development and effector function. These studies have highlighted the unique requirements for the activation of these lymphocytes and the functional responses that distinguish these cells from other effector lymphocyte populations such as conventional T cells and NK cells. This body of literature suggests that NKT cells play diverse nonredundant roles in a number of disease processes, including the initiation and propagation of airway hyperreactivity, protection against a variety of pathogens, development of autoimmunity, and mediation of allograft responses. In this review, however, we focus on the role of a specific lineage of NKT cells in antitumor immunity. Specifically, we describe the development of invariant NKT (iNKT) cells and the factors that are critical for their acquisition of effector function. Next, we delineate the mechanisms by which iNKT cells influence and modulate the activity of other immune cells to directly or indirectly affect tumor growth. Finally, we review the successes and failures of clinical trials employing iNKT cell-based immunotherapies and explore the future prospects for the use of such strategies.
    Full-text · Article · Oct 2015 · Journal of Immunology Research
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