scholarly journals Hiding Lipid Presentation: Viral Interference with CD1d-Restricted Invariant Natural Killer T (iNKT) Cell Activation

Viruses ◽  
2012 ◽  
Vol 4 (10) ◽  
pp. 2379-2399 ◽  
Author(s):  
Daniëlle Horst ◽  
Ruben J. Geerdink ◽  
Anna M. Gram ◽  
Arie J. Stoppelenburg ◽  
Maaike E. Ressing
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Inkt Cell ◽  
Viral Interference ◽  
Lipid Presentation ◽  
Invariant Natural Killer ◽  
Natural Killer T

scholarly journals Cancer Immunotherapeutic Potential of NKTT320, a Novel, Invariant, Natural Killer T Cell-Activating, Humanized Monoclonal Antibody

2020 ◽  
Vol 21 (12) ◽  
pp. 4317 ◽  
Author(s):  
Nishant P. Patel ◽  
Peng Guan ◽  
Devika Bahal ◽  
Tanwir Hashem ◽  
Felix Scheuplein ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Natural Killer ◽  
Cell Activation ◽  
Cell Receptor ◽  
Inkt Cell ◽  
Humanized Monoclonal Antibody ◽  
Cancer Immunotherapeutic ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.

Abstract 541: Specific Deletion of LDL Receptor--Related Protein on Macrophages Skews Cytokine Production by Invariant Natural Killer T Cells

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Roman Covarrubias ◽  
Amy S Major
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Ldl Receptor ◽  
Inkt Cell ◽  
Related Protein ◽  
Inkt Cells ◽  
Glycolipid Antigen ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant Natural Killer T (iNKT) cells are specialized lymphocytes that when activated can regulate chronic inflammatory conditions and atherosclerotic processes. The activation of iNKT cells occurs when glycolipid antigens bind the MHC class-I like molecule CD1d present on antigen presenting cells (APCs). The pathways by which glycolipid antigens target CD1d for presentation and activation of iNKT cells remain unclear, yet the expression of surface receptors associated with lipid homeostasis, such as the LDL receptor (LDLr), have been implicated in the modulation of iNKT cell activation. The LDLr has been shown to modulate this process by binding apoE-containing lipoproteins, which can carry antigenic glycolipids for iNKT cell activation. The LDL receptor-related protein (LRP), a transmembrane receptor from the LDL receptor family of proteins, shares structural homology with LDLr and can bind a number of ligands including apoE-containing lipoproteins. We hypothesized that LRP can play an active role in glycolipid antigen presentation and subsequent activation of iNKT cells. Here, we demonstrate that LRP is preferentially expressed at high levels on F4/80 + macrophages, when compared to other APCs. We also show that a specialized subset of macrophages expressing CD169, known for their ability to present glycolipid antigen to iNKT cells, have increased levels of LRP when compared to CD169 - macrophages. Using mice with a targeted deletion of LRP in macrophages, we observed decreased activation of iNKT cells in vitro (24, 48 hours) and normal IFN-gamma but blunted IL-4 response in vivo. Further flow cytometric analysis showed normal surface expression of CD1d in LRP-cKO macrophages as well as normal uptake of fluorescently labeled glycolipid in vitro . Additionally, analysis of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages of iNKT cells and no homeostatic disruption as evidenced by absence of programmed death-1 and LY-49. Collectively, these data suggest that macrophage LRP contributes to early iNKT cell activation by enhancing early IL-4 responses.

scholarly journals Longitudinal analysis of invariant natural killer T cell activation reveals a cMAF-associated transcriptional state of NKT10 cells

2021 ◽  
Author(s):  
Lydia Lynch ◽  
Harry Kane ◽  
Nelson M LaMarche ◽  
Áine Ní Scannail ◽  
Michael P. Brenner
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inkt Cell ◽  
Inkt Cells ◽  
Innate T Cells ◽  
Nonpeptide Antigens ◽  
Invariant Natural Killer ◽  
Natural Killer T

Innate T cells, including CD1d-restricted invariant natural killer T (iNKT) cells, are characterized by their rapid activation in response to nonpeptide antigens, such as lipids. While the transcriptional profiles of naive, effector and memory adaptive T cells have been well studied, less is known about transcriptional regulation of different iNKT cell activation states. Here, using single cell RNA-sequencing, we performed longitudinal profiling of activated iNKT cells, generating a transcriptomic atlas of iNKT cell activation states. We found that transcriptional signatures of activation are highly conserved among heterogeneous iNKT cell populations, including NKT1, NKT2 and NKT17 subsets, and human iNKT cells. Strikingly, we found that regulatory iNKT cells, such as adipose iNKT cells, undergo blunted activation, and display constitutive enrichment of memory-like cMAF+ and KLRG1+ populations. Moreover, we identify a conserved cMAF-associated transcriptional network among NKT10 cells, providing novel insights into the biology of regulatory and antigen experienced iNKT cells.

scholarly journals Expression of signal-transducing adaptor protein-1 attenuates experimental autoimmune hepatitis via down-regulating activation and homeostasis of invariant natural killer T cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241440
Author(s):  
Jun-ichi Kashiwakura ◽  
Kodai Saitoh ◽  
Takeru Ihara ◽  
Yuto Sasaki ◽  
Kota Kagohashi ◽  
...  
Keyword(s):  
Autoimmune Hepatitis ◽  
Natural Killer ◽  
Cell Activation ◽  
Adaptor Protein ◽  
Interferon Γ ◽  
Inkt Cell ◽  
Interleukin 4 ◽  
Con A ◽  
Invariant Natural Killer ◽  
Natural Killer T

Objective Signal-transducing adaptor protein (STAP) family members function as adaptor molecules and are involved in several events during immune responses. Notably however, the biological functions of STAP-1 in other cells are not known. We aimed to investigate the functions of STAP-1 in invariant natural killer T (iNKT) cells and iNKT cell-dependent hepatitis. Methods We employed concanavalin A (Con A)-induced hepatitis and α-galactosylceramide (α-GalCer)-induced hepatitis mouse models, both are models of iNKT cell-dependent autoimmune hepatitis, and STAP-1 overexpressing 2E10 cells to investigate the role of STAP-1 in iNKT cell activation in vivo an in vitro, respectively. Results After Con A- or α-GalCer-injection, hepatocyte necrotic areas and plasma alanine aminotransferase elevation were more severe in STAP-1 knockout (S1KO) mice and milder in lymphocyte-specific STAP-1 transgenic (S1Tg) mice, as compared to wild-type (WT) mice. Two events that may be related to Con A-induced and/or α-GalCer-induced hepatitis were influenced by STAP-1 manipulation. One is that iNKT cell populations in the livers and spleens were increased in S1KO mice and were decreased in S1Tg mice. The other is that Con A-induced interleukin-4 and interferon-γ production was attenuated by STAP-1 overexpression. These effects of STAP-1 were confirmed using 2E10 cells overexpressing STAP-1 that showed impairment of interleukin-4 and interferon-γ production as well as phosphorylation of Akt and mitogen-activated protein kinases in response to Con A stimulation. Conclusions These results conclude that STAP-1 regulates iNKT cell maintenance/activation, and is involved in the pathogenesis of autoimmune hepatitis.

scholarly journals Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection

2011 ◽  
Vol 208 (6) ◽  
pp. 1163-1177 ◽  
Author(s):  
Manfred Brigl ◽  
Raju V.V. Tatituri ◽  
Gerald F.M. Watts ◽  
Veemal Bhowruth ◽  
Elizabeth A. Leadbetter ◽  
...  
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Constitutive Expression ◽  
Microbial Pathogens ◽  
Inkt Cell ◽  
Microbial Infection ◽  
Inkt Cells ◽  
Natural Killer T

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.

scholarly journals Invariant natural killer T (iNKT) cell exhaustion in sarcoidosis

2013 ◽  
Vol 43 (8) ◽  
pp. 2194-2205 ◽  
Author(s):  
Jennifer E. Snyder-Cappione ◽  
Douglas F. Nixon ◽  
Joyce C. Chi ◽  
Michelle-Linh T. Nguyen ◽  
Christopher K. Kirby ◽  
...  
Keyword(s):  
Natural Killer ◽  
Inkt Cell ◽  
Cell Exhaustion ◽  
Invariant Natural Killer ◽  
Natural Killer T

scholarly journals Distinct bioenergetic features of human invariant natural killer T (iNKT) cells enable retained functions in nutrient-deprived states

2021 ◽  
Author(s):  
Priya Khurana ◽  
Chakkapong Burudpakdee ◽  
Stephan A. Grupp ◽  
Ulf H. Beier ◽  
David M. Barrett ◽  
...  
Keyword(s):  
Natural Killer ◽  
Metabolic Flux ◽  
Cytokine Production ◽  
Inkt Cell ◽  
Flux Analysis ◽  
Inkt Cells ◽  
Effector Functions ◽  
Functional Features ◽  
Invariant Natural Killer ◽  
Natural Killer T

ABSTRACTInvariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (TCONV), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect cytokine production or anti-tumor effector functions. We find that unlike TCONV, human iNKT cells are not dependent upon glucose or glutamine for cytokine production and cytotoxicity upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than TCONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to TCONV. Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated TCONV. Together, our data suggest that human iNKT cells possess different bioenergetic requirements from TCONV and display a more memory-like metabolic program relative to effector TCONV. Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.

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