The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian α-Linked Glycosylceramides

Kain, Lisa; Webb, B. D.; Anderson, Brian L.; Deng, Shenglou; Holt, Marie K.; Costanzo, Anne; Zhao, Meng; Self, Kevin; Teyton, Anaïs; Everett, Chris; Kronenberg, Mitchell; Zajonc, Dirk M.; Bendelac, Albert; Savage, Paul B.; Teyton, Luc

doi:10.1016/j.immuni.2014.10.014

Cited by 3 publications

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“…iNKT cells are the major type of NKT cell found in mouse liver [2]. iNKT cells are rapidly activated by a number of stimuli, including lipid antigens; a process mimicked by administration of the glycolipid αGalCer, which is also an endogenous iNKT cell ligand [5,8,38]. The rapid activation of iNKT cells has been critically linked to the regulation of hepatic immunity, in both humans and animal models [11,19,33,[39][40][41].…”

Section: Discussionmentioning

confidence: 99%

“…Activated iNKT cells rapidly produce numerous cytokines which critically regulate downstream immune processes within the liver [1,2,5,6]. This iNKT cell-associated hepatic immune activation is mimicked by the administration of the glycolipid alpha galactosylceramide (αGalCer) [5,7]; an endogenous iNKT cell ligand [8]. iNKT cell activation also results in the activation and recruitment of numerous other innate (eg.…”

Section: Introductionmentioning

confidence: 99%

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Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

Almishri¹,

Deans

Swain

2015

Journal of Hepatology

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

Almishri¹,

Deans

Swain

2015

Journal of Hepatology

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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.…”

Section: The Characterization Of Inkt Cell Antigensmentioning

confidence: 99%

From the Deep Sea to Everywhere: Environmental Antigens for iNKT Cells

Wingender

2015

Arch. Immunol. Ther. Exp.

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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.

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“…The Asp93 residue of GalA interacts with the 6'-OH of galactose inside the binding pocket. However, GalA cannot directly hydrolyse aGalCer without the removal of the acyl chain to form agalactosylsphingosine, which can be hydrolysed by GalA [434] . It's likely that this step is hydrolysed by acid ceramidase 1 (ASAH1) to form a-galactosylsphingosine, which is a more available substrate for GalA, as ASAH1 inhibition can also lead to NKT cell activation.…”

Section: Discussionmentioning

confidence: 99%

“…It's likely that this step is hydrolysed by acid ceramidase 1 (ASAH1) to form a-galactosylsphingosine, which is a more available substrate for GalA, as ASAH1 inhibition can also lead to NKT cell activation. Furthermore, Gla (encoding GalA) knockout experiments have shown that GalA is important in regulation of endogenous glycolipids that stimulate NKT cells [435] , which have later been shown to be aGalCer [434] . GalA has an important role in NKT cell development and function, demonstrated individuals with Fabry disease (GalA deficiency) and mouse models that have a pro-inflammatory phenotype [436] .…”

Section: Discussionmentioning

confidence: 99%

Generation of liver tissue-resident memory T cells with novel NKT cell agonists and mRNA vaccines

Ganley

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<p dir="ltr">mRNA vaccines have become a central part of vaccine research over the last decade due to their application in cancer immunotherapy, and more recently, the rapid response to the SARS-CoV-2 pandemic leading to two clinically approved mRNA vaccines that generate cellular and humoral immunity. These vaccines have saved countless lives and have paved the way for the prevention and treatment of infectious diseases with new mRNA vaccines. One area of ongoing investigation is the longevity and specificity of the adaptive immune response which incorporates both humoral (i.e. antibody) and cellular (T cell) memory. Whilst the focus of the SARS-CoV-2 vaccines was humoral-mediated immunity another emerging field of immunology and vaccine development is the function and generation of tissue-resident memory T(rm) cells. These specialised memory cells reside in tissues awaiting the presence of a pathogen and “raise the alarm” when they encounter the pathogen. This involves the production of inflammatory cytokines that attract other circulating immune cells and have a rapid cytotoxic function that eliminates infected cells. Previous work has shown that the activation of “innate-like” natural killer T (NKT) cells can improve adaptive immune responses, including the production of Trm cells in the liver that can provide sterile protection from malaria sporozoites. This work explored the use of and effect on the adaptive cellular immune system of vaccines comprising NKT cell agonists and mRNA encoding pathogen antigens co-delivered in lipid-delivery vehicles. The inclusion of an NKT cell agonist improved the generation of circulating effector memory CD8+ T(em) cells and the type of ligand affected the magnitude of the priming effector response. Surprisingly, whilst the magnitude of Tem responses generally predicted other memory responses, liver Trm responses were detached from priming responses with regard to specific agonist compounds. In particular, several novel NKT cell agonists, including CI058 generated substantially more liver Trm than the prototypical NKT cell agonist, aGalCer, even though aGalCer induced stronger priming Tem responses. The liver Trm inducing capacity of the novel NKT cell agonists was dependent on modification at the 6’ position of the galactose of a-linked glycolipids. The vaccines developed during this work were able to generate protective liver Trm that could be boosted and protect from Plasmodium sporozoite challenge to model and disease-relevant Plasmodium antigens. Additionally, global research efforts have demonstrated vaccine or infection-acquired immunity (antibody or liver Trm) is impaired by previous red blood cell (RBC) infection by Plasmodium. In contrast, the liver CD8+ Trm cells generated by these NKT cell-adjuvanted mRNA vaccines were unaffected by previous RBC infection. The specific signals from NKT cells that contribute to this improvement in liver Trm formation are unclear, but the response is dependent on both the mRNA vaccine and NKT cell signalling. The response was abrogated in the absence of NKT cells and its magnitude was dependent on a NKT cell phenotype. Modulation of the mRNA component could either impair or improve the overall response and there is synergy between NKT cell and TLR signalling in DC licencing and IL-12 production that positively correlates with liver Trm.</p>

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The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian α-Linked Glycosylceramides

Cited by 3 publications

References 0 publications

Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

Rapid activation and hepatic recruitment of innate-like regulatory B cells after invariant NKT cell stimulation in mice

From the Deep Sea to Everywhere: Environmental Antigens for iNKT Cells

Generation of liver tissue-resident memory T cells with novel NKT cell agonists and mRNA vaccines

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