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Obesity is accompanied by inflammation in adipose tissue, impaired glucose tolerance, and changes in adipose leukocyte populations. These studies of adipose tissue from humans and mice revealed that increased frequencies of T-bet+ B cells in adipose tissue depend on invariant NKT cells and correlate with weight gain during obesity. Transfer of B cells enriched for T-bet+ cells exacerbates metabolic disorder in obesity, while ablation of Tbx21 specifically in B cells reduces serum IgG2c levels, inflammatory cytokines, and inflammatory macrophages in adipose tissue, ameliorating metabolic symptoms. Furthermore, transfer of serum or purified IgG from HFD mice restores metabolic disease in T-bet+ B cell-deficient mice, confirming T-bet+ B cell-derived IgG as a key mediator of inflammation during obesity. Together, these findings reveal an important pathological role for T-bet+ B cells that should inform future immunotherapy design in type 2 diabetes and other inflammatory conditions. • Activated T-bet+ B cells accumulate in adipose tissue of humans and mice with obesity • iNKT cells support adipose accumulation and antibody production by T-bet+ B cells • Mice lacking T-bet+ in B cells are protected from metabolic symptoms of obesity • HFD-fed mouse IgG restores metabolic disease in obese mice lacking T-bet+ B cells Hägglöf et al. dissect the role of T-bet+ B cells in exacerbating metabolic disorder during obesity. Specifically, T-bet+ B cells accumulate during progressing obesity in mice and humans. B cell-targeted deletion of Tbx21 significantly ameliorates metabolic disorder in obese mice, but it can be restored by transfer of HFD IgG. [ABSTRACT FROM AUTHOR]

Activation of mTORC1 is essential for anti-tumor function of iNKT cells. The mechanisms underlying impaired mTORC1 activation in intratumoral iNKT cells remain unclear. Via generating Vam6 +/- mice and using flow cytometry, image approach, and RNA sequencing, we studied the role of Vam6 in controlling mTORC1 activation and intratumoral iNKT cell functions. Here, we find that increased Vam6 expression in intratumoral iNKT cells leads to impaired mTORC1 activation and IFN-γ production. Mechanistically, Vam6 in iNKT cells is essential for Rab7a-Vam6-AMPK complex formation and thus for recruitment of AMPK to lysosome to activate AMPK, a negative regulator of mTORC1. Additionally, Vam6 relieves inhibitory effect of VDAC1 on Rab7a-Vam6-AMPK complex formation at mitochondria-lysosome contact site. Moreover, we report that lactic acid produced by tumor cells increases Vam6 expression in iNKT cells. Given the key roles of increased Vam6 in promoting AMPK activation in intratumoral iNKT cells, reducing Vam6 expression signifificantly enhances the mTORC1 activation in intratumoral iNKT cells as well as their anti-tumor effificacy. Together, we propose Vam6 as a target for iNKT cell-based immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bai, Wu, Zhu, Zhang, Chen, Su, Pan, Li, Yue, Xu, Xie, Tian, Zhao, Li, Hou, Wang, Fu, Xue, Jiang, Li, Xu, Tian, Zhou, Zhang and Bai.)

Certain glycolipids have immunomodulatory potential by activating natural killer T (NKT) cells, a unique T cell subset. Invariant NKT (iNKT) cells recognize α-galactosylceramide (α-GalCer) and synthetic derivatives presented by CD1d molecules and secrete large amounts of cytokines that modulate immune functions. Some iNKT cell ligands induce distinct reactions biased toward either Th1 or Th2 immune responses, while others show mixed responses. We describe the methods for activating iNKT cells by the ligands as represented by α-GalCer using in vitro assays, such as cell-free or co-culture with antigen-presenting cells. In addition, α-GalCer/CD1d multimer can be used to specifically detect iNKT cells using flow cytometry. α-GalCer is also utilized to activate systemic iNKT cells in vivo, which leads to the production of high levels of cytokines in sera. Collectively, α-GalCer and its derivatives activate iNKT cells that modulate immune balance, and we need to understand the characteristics of these ligands for developing their utility., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Invariant Natural Killer T (iNKT) cells have been implicated in lung inflammation in humans and also shown to be a key cell type in inducing allergic lung inflammation in mouse models. iNKT cells differentiate and acquire functional characteristics during development in the thymus. However, the correlation between development of iNKT cells in the thymus and role in lung inflammation remains unknown. In addition, transcriptional control of differentiation of iNKT cells into iNKT cell effector subsets in the thymus during development is also unclear. In this report we show that β-catenin dependent mechanisms direct differentiation of iNKT2 and iNKT17 subsets but not iNKT1 cells. Methods: To study the role for β-catenin in lung inflammation we utilize mice with conditional deletion and enforced expression of β-catenin in a well-established mouse model for IL-25-dependen lung inflammation. Results: Specifically, we demonstrate that conditional deletion of β-catenin permitted development of mature iNKT1 cells while impeding maturation of iNKT2 and 17 cells. A role for β-catenin expression in promoting iNKT2 and iNKT17 subsets was confirmed when we noted that enforced transgenic expression of β-catenin in iNKT cell precursors enhanced the frequency and number of iNKT2 and iNKT17 cells at the cost of iNKT1 cells. This effect of expression of β-catenin in iNKT cell precursors was cell autonomous. Furthermore, iNKT2 cells acquired greater capability to produce type-2 cytokines when β-catenin expression was enhanced. Discussion: This report shows that β-catenin deficiency resulted in a profound decrease in iNKT2 and iNKT17 subsets of iNKT cells whereas iNKT1 cells developed normally. By contrast, enforced expression of β-catenin promoted the development of iNKT2 and iNKT17 cells. It was important to note that the majority of iNKT cells in the thymus of C57BL/6 mice were iNKT1 cells and enforced expression of β-catenin altered the pattern to iNKT2 and iNKT17 cells suggesting that β-catenin may be a major factor in the distinct pathways that critically direct differentiation of iNKT effector subsets. Conclusions: Thus, we demonstrate that β-catenin expression in iNKT cell precursors promotes differentiation toward iNKT2 and iNKT17 effector subsets and supports enhanced capacity to produce type 2 and 17 cytokines which in turn augment lung inflammation in mice. [ABSTRACT FROM AUTHOR]

Successful induction of B-cell activation and memory depends on help from CD4+ T cells. Invariant natural killer T (iNKT) cells (glycolipid-specific, CD 1d-restricted innate lymphocytes) provide both cognate (direct) and noncognate (indirect) helper signals to enhance B-cell responses. Both forms of iNKT-cell help induce primary humoral immune responses, but only noncognate iNKT-cell help drives humoral memory and plasma cells. Here, we show that iNKT cognate help for B cells is fundamentally different from the help provided by conventional CD4+ T cells. Cognate iNKT-cell help drives an early, unsustained germinal center B-cell expansion, less reduction of T follicular regulatory cells, an expansion of marginal zone B cells, and early increases in regulatory IL-10-producing B-cell numbers compared with noncognate activation. These results are consistent with a mechanism whereby iNKT cells preferentially provide an innate form of help that does not generate humoral memory and has important implications for the application of glycolipid molecules as vaccine adjuvants. [ABSTRACT FROM AUTHOR]

Background: Invariant Natural Killer T (iNKT) cells belong to innate immunity and combine T-cell receptor specificity with Natural Killer surface markers. They can produce cytokines immediately after stimulation and direct immunity to either Th1 or Th2 cytokine production. iNKT cells participate in a variety of immune responses, such as microbial infections, autoimmunity, and cancer. Type 2 Diabetes Mellitus (T2DM) has been associated with activated innate immunity and certain cytokine profile during microbial infections. This study aimed to evaluate whether iNKT cells have a role in the immune response of T2DM patients during infections with gram-negative bacteria. Method: The T2DM group consisted of patients (n =11) who had a diagnosis of T2DM for at least six months and febrile illness for three days, while the control group consisted of patients (n =11) who had not T2DM, but were febrile for three days. All patients were infected by gram-negative bacteria. Physical examination was performed, and peripheral blood was drawn on days three and six of febrile illness. Flow cytometry was utilized for iNKT cell identification with monoclonal antibodies Phycoerythrin (PE) - Cyanin (CY) 5 anti-Human CD3, Fluorescein isothiocyanate (FITC) anti-Human CD4, PE anti-human invariant NKT T-Cell Receptor. For intracellular staining, we used Alexa Fluor anti-Human interferon-? (IFN-?) and Allophycocyanin (APC) anti-human interleukin-4 (IL-4). The variables processed were: CD3+IL-4+iNKT+, CD4+IL-4+iNKT+, CD3+IFN?+iNKT+, CD4+IFN?+i???+, CD3+iNKT+, CD4+iNKT+,CD3+IL4+, CD4+IL-4+, CD3+IFN?+, CD4+IFN?+ on days three and six of febrile illness (CD3+, CD4+: T lymphocyte surface markers, iNKT+: invariant Natural Killer T- Cell Receptor, IL4+: interleukin 4, IFNγ+: interferon γ). Results: Comparisons between T2DM patients and controls revealed no statistically significant difference in any of the study's variable. Regarding within T2DM patients comparisons CD4+IL4+iNKT+, CD3+IL4+iNKT+, CD4+IFN+iNKT+, CD3+IFN+iNKT+, and CD3+iNKT+ decreased, whereas CD3+IL4+ was increased at day six compared to day three. Within control group CD4+IL4+iNKT+, CD3+IL4+iNKT+, and CD3+iNKT+ were decreased, whereas CD4+IFN+, CD3+IFN+ were increased at day six compared to day three. Conclusion: The absence of statistical difference between T2DM patients and controls implies that the role of iNKT cells is virtually the same in both groups of patients during the course of gram-negative infections and that there is no numerical variance of this cell population between the two groups. Despite the small sample size, we notice that all iNKT parameters (both IL4/IFN?) are suppressed in the T2DM group during the later phase, but only those concerning IL4+iNKT+ in the control group, suggesting that IFN? production remains elevated in the controls. A compensatory anti-inflammatory type-response could provide an explanation for the prevalence of IL4 production during the later phase of infection in T2DM and the sustained production of IFN? in controls. [ABSTRACT FROM AUTHOR]

TCRs of invariant NKT (iNKT) cells bind α-galactosylceramide (αGC) loaded CD1d in a highly conserved fashion and show a characteristic TCR gene usage: An 'invariant' α chain with a canonical AV14/ AJ18 rearrangement in mice ( AV24/ AJ18 in humans) is paired with β chains containing characteristic Vβ segments. In the rat, a multimember AV14 gene family increases the variability within this system. This study characterizes CD1d binding of rat AV14 gene segments in TCR transductants as well as CD1d binding and iNKT TCR expression of expanded polyclonal F344 rat iNKT populations. It defines an important role of position 93 at the V-J transition for TCR avidity and species cross-reactivity of the rat iNKT TCR. Furthermore, for the first time we identified variability within the fourth hypervariable loop (HV4) of the α chain as a modulator of CD1d:αGC binding in rat and mouse. Additionally, we confirmed the importance of the CDR2β for CD1d:αGC binding, but also show that the CDR3β may even have opposite effects on binding depending on the pairing α chain. Altogether, we characterized naturally occurring sources of variability for the iNKT TCR and speculate that they rather level than increase the largely germline encoded differences of iNKT TCR ligand avidity. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) and type 2 diabetes (T2D) are multifactorial diseases with different etiologies in which chronic inflammation takes place. Defects in invariant natural killer T (iNKT) cell populations have been reported in both T1D and T2D patients, mouse models and our recent study revealed mucosal-associated invariant T (MAIT) cell defects in T2D and obese patients. Regarding iNKT cells many studies in non-obese diabetic mice demonstrated their protective role against T1D whereas their potential role in human T1D is still under debate. Studies in mouse models and patients suggest that iNKT cells present in adipose tissue (AT) could exert a regulatory role against obesity and associated metabolic disorders, such as T2D. Scarce data are yet available on MAIT cells; however, we recently described MAIT cell abnormalities in the blood and ATs from obese and T2D patients. These data show that a link between MAIT cells and metabolic disorders pave the way for further investigations on MAIT cells in T1D and T2D in humans and mouse models. Furthermore, we hypothesize that the gut microbiota alterations associated with T1D and T2D could modulate iNKT and MAIT cell frequency and functions. The potential role of iNKT and MAIT cells in the regulation of metabolic pathways and their cross-talk with microbiota represent exciting new lines of research. [ABSTRACT FROM AUTHOR]

A key role for the IL-23/IL-17 immune axis in spondyloarthritis (SpA) is supported by cumulative evidence from genetic and translational studies and was recently confirmed in clinical trials. Although initially linked to T helper 17 cells, it is now clear that additional unconventional T cell subpopulations respond towards IL-23, including RORγt CD3CD4CD8 T cells, TCRγδ17 cells, KIR3DL2CD4 T cells and iNKT17 cells. Although these innate-like T cells are present only at low frequencies and often with a specific tissue distribution, it is proposed that they could play a vital function in the development or progression of SpA-related pathology. In this review, we highlight the emerging knowledge on these specialized IL-23 responsive T cells with regard to their relevance in SpA. Finally, we will discuss these findings in light of novel drugs targeting the IL-23/IL-17 axis, currently being tested in SpA patients. [ABSTRACT FROM AUTHOR]

Natural killer T cells (NKT cells) are effector cells, but also regulator of immune response, which either promote or suppress immune response through production of different cytokines. However, the subsets of NKT cells with definite phenotype and regulatory function need to be further identified. Furthermore, the mechanisms for NKT cells to regulate immune response remain to be fully elucidated. Here we identified CD11b + invariant NKT (CD11b + iNKT) cells as a new subset of regulatory NKT cells in mouse models with infection. αGalCer:CD1d complex + TCRβ + NK1.1 + NKT cells could be categorized to CD11b + and CD11b − subsets. NKT cells are enriched in liver. During Listeria monocytogenes infection, hepatic CD11b + iNKT cells were significantly induced and expanded, with peak expansion on day 8. CD11b + iNKT cells were also expanded significantly in spleen and mesenteric lymph nodes. As compared to CD11b − iNKT cells, CD11b + iNKT cells expressed higher levels of CD27, FasL, B7H1, CD69, and particularly higher level of membrane-bound TGF-β1 (mTGF-β1), but produced less IFN-γ, IL-4, IL-10 and TGF-β1. Hepatic CD11b + iNKT cells suppressed antigen-nonspecific and OVA-specific CD4 and CD8 T cell proliferation through mTGF-β1 both in vitro and in vivo , meanwhile, they did not interfere with activation of CD4 T cells and cytotoxicity of the activated CD8 T cells. Thus, we have identified a new subset of pathogen-expanded CD11b + invariant NKT cells which can feedback inhibit T cell response through cell-to-cell contact via cell surface (membrane-bound) TGF-β1, especially at the late stage of immune response against infection. CD11b + regulatory iNKT cells may contribute to protect host from pathological injure by preventing immune overactivation. [ABSTRACT FROM AUTHOR]

IL-18 is induced in food allergy and EoE is food allergen-induced disease. Therefore, we tested the hypothesis whether IL-18 is involved in food allergen-induced EoE pathogenesis. Accordingly, we examined normal SPT + and SPT − EoE patient blood and biopsy samples for IL-18, IL-18Rα, ICAM and VCAM expression. Herein, we show increased IL-18 level is highly significant in food allergen SPT + compared to SPT − EoE patients. We also report that IL-18Rα + cells and mRNA levels are induced in the esophageal biopsies of EoE patients and blood IL-18 levels correlate with esophageal eosinophilia (P < 0.01). Additionally, we report that the levels of esophageal eosinophil and mast cells correlate with ICAM expression in human EoE. Mechanistically, we show that IL-18 in vitro stimulates iNKT cells and endothelial cells and induce eosinophil active cytokines IL-5 and IL-13. We provide the evidence that IL-18 is critical cytokine involved in activation of iNKT cells and ICAM in promoting human EoE. [ABSTRACT FROM AUTHOR]

The organization of the thymus into distinct cortical and medullary regions enables it to control the step-wise migration and development of immature T-cell precursors. Such a process provides access to specialized cortical and medullary thymic epithelial cells at defined stages of maturation, ensuring the generation of self-tolerant and MHC-restricted conventional CD4+ and CD8+ αβ T cells. The migratory cues and stromal cell requirements that regulate the development of conventional αβ T cells have been well studied. However, the thymus also fosters the generation of several immunoregulatory T-cell populations that form key components of both innate and adaptive immune responses. These include Foxp3+ natural regulatory T cells, invariant γδ T cells, and CD1d-restricted invariant natural killer T cells (iNKT cells). While less is known about the intrathymic requirements of these nonconventional T cells, recent studies have highlighted the importance of the thymus medulla in their development. Here, we review recent findings on the mechanisms controlling the intrathymic migration of distinct T-cell subsets, and relate this to knowledge of the microenvironmental requirements of these cells. [ABSTRACT FROM AUTHOR]

Background: LAG-3 is a potent negative regulator of the immune response but its impact in HIV infection in poorly understood. Unlike exhaustion markers such as PD-1, Tim-3, 2B4 and CD160, LAG-3 is poorly expressed on bulk and antigen-specific T cells during chronic HIV infection and its expression on innate lymphocyte subsets is not well understood. The aim of this study was to assess LAG-3 expression and association with cellular dysfunction on T cells, NK cells and iNKT cells among a cohort of healthy and HIV-infected female sex workers in Nairobi, Kenya. Results: Ex vivo LAG-3 expression was measured by multiparametric flow cytometry, and plasma cytokine/chemokine concentrations measured by bead array. Although LAG-3 expression on bulk T cells was significantly increased among HIV-infected women, the proportion of cells expressing the marker was extremely low. In contrast, LAG-3 was more highly expressed on NK and iNKT cells and was not reduced among women treated with ART. To assess the functional impact of LAG-3 on iNKT cells, iNKT cytokine production was measured in response to lipid (aGalCer) and PMA/Io stimulation by both flow cytometry and cytokine bead array. iNKT cytokine production is profoundly altered by both HIV infection and treatment, and LAG-3, but not PD-1, expression is associated with a reduction in iNKT IFN? production. Conclusions: LAG-3 does not appear to mediate T cell exhaustion in this African population, but is instead expressed on innate lymphocyte subsets including iNKT cells. HIV infection alters iNKT cytokine production patterns and LAG-3 expression is uniquely associated with iNKT dysfunction. The continued expression of LAG-3 during treatment suggests it may contribute to the lack of innate immune reconstitution commonly observed during ART. [ABSTRACT FROM AUTHOR]

IgG autoantibodies, including antibodies to double-stranded DNA (dsDNA), are pathogenic in systemic lupus erythematosus (SLE), but the mechanisms controlling their production are not understood. To assess the role of invariant natural killer T (iNKT) cells in this process, we studied 44 lupus patients. We took advantage of the propensity of PBMCs from patients with active disease to spontaneously secrete IgG in vitro. Despite the rarity of iNKT cells in lupus blood (0.002-0.05% of CD3-positive T cells), antibody blockade of the conserved iNKT TCR or its ligand, CD1d, or selective depletion of iNKT cells, inhibited spontaneous secretion of total IgG and anti-dsDNA IgG by lupus PBMCs. Addition of anti-iNKT or anti-CD1d antibody to PBMC cultures also reduced the frequency of plasma cells, suggesting that lupus iNKT cells induce B-cell maturation. Like fresh iNKT cells, expanded iNKT-cell lines from lupus patients, but not healthy subjects, induced autologous B cells to secrete antibodies, including IgG anti-dsDNA. This activity was inhibited by anti-CD40L antibody, as well as anti-CD1d antibody, confirming a role for CD40L-CD40 and TCR-CD1d interactions in lupus iNKT-cell-mediated help. These results reveal a critical role for iNKT cells in B-cell maturation and autoantibody production in patients with lupus. [ABSTRACT FROM AUTHOR]

Commonvariable immunodeficiency (CVID) is one of the most common and clinically important primary immune deficiencies. CVID patients have poor humoral immunity, resulting in recurrent infections of the gastrointestinal and upper respiratory tracts, aswell as increased incidence of some forms of cancers and autoimmune diseases. The treatment for CVID is IgG replacement, often given as intravenous immunoglobulins (IVIg). IVIg consists of monomeric IgG purified from pooled plasma from healthy donors and is used to treat an increasing number of conditions including autoimmune diseases. In the case of CVID, IVIg has mainly been seen as reconstitution therapy, providing patients with pathogen-specific antibodies. Recent evidence shows that IVIg has diverse effects on the immune system of CVID patients, and one important component is that IVIg alleviates the state of chronic immune activation. In this review, we will discuss causes and consequences of persistent immune activation in CVID, possible underlying mechanisms for how IVIg treatment reduces immune activation, and implications for our understanding of primary as well as acquired immune deficiencies. [ABSTRACT FROM AUTHOR]

The identification of DC-derived signals orchestrating activation of Th1 and Th17 immune responses has advanced our understanding on how these inflammatory responses develop. However, whether specific signals delivered by DCs also participate in the regulation of Th2 immune responses remains largely unknown. In this study, we show that administration of antigen-loaded, IL-6-deficient DCs to naïve mice induced an exacerbated Th2 response, characterized by the differentiation of GATA-3-expressing T lymphocytes secreting high levels of IL-4, IL-5, and IL-13. Coinjection of wild type and IL-6-deficient bone marrow-derived dendritic cells (BMDCs) confirmed that IL-6 exerted a dominant, negative influence on Th2-cell development. This finding was confirmed in vitro, where exogenously added IL-6 was found to limit IL-4-induced Th2-cell differentiation. iNKT cells were required for optimal Th2-cell differentiation in vivo although their activation occurred independently of IL-6 secretion by the BMDCs. Collectively, these observations identify IL-6 secretion as a major, unsuspected, mechanism whereby DCs control the magnitude of Th2 immunity. [ABSTRACT FROM AUTHOR]

Innate T cells, including CD1d-restricted invariant natural killer T (iNKT) cells, are characterized by their rapid activation in response to non-peptide antigens, such as lipids. While the transcriptional profiles of naive, effector, and memory adaptive T cells have been well studied, less is known about the transcriptional regulation of different iNKT cell activation states. Here, using single-cell RNA-sequencing, we performed longitudinal profiling of activated murine 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., Competing Interests: HK, NL, ÁN, AG, HK, AA, BK, BS, MB, LL No competing interests declared, (© 2022, Kane et al.)

Background/aim: Invariant natural killer T (iNKT) cells are involved in the initiation and resolution of inflammatory responses. We previously reported that activated iNKT cells facilitate liver repair after hepatic ischemia reperfusion (I/R) injury by accelerating macrophage polarization during the early phase of hepatic I/R injury. Upon activation with α-galactosylceramide (α-GalCer), iNKT cell numbers transiently decrease before increasing within 72 h of stimulation. In the present study, we examined the role of expanded hepatic iNKT cells in the late phase of hepatic I/R injury., Materials and Methods: iNKT cells were activated by intraperitoneal injection of α-GalCer in male C57/BL6 mice at the induction of hepatic ischemia followed by reperfusion., Results: Numbers of activated hepatic iNKT cells immediately diminished after hepatic I/R and reached minimal levels at 24 h and 48 h post-reperfusion. Numbers of hepatic iNKT cells then increased at 72 h and 96 h post-reperfusion to levels approximately 2-fold higher than in mice that underwent a sham operation. Liver repair as demonstrated by decreased necrotic area and increased expression of proliferating cell nuclear antigen (PCNA) was enhanced in α-GalCer-treated mice at 96 h post-reperfusion. Interleukin (IL)-13 production by proliferating iNKT cells was observed at 96 h post-reperfusion, which was associated with enhanced liver repair and increased numbers of reparative macrophages., Conclusion: Repopulation of hepatic iNKT cells promotes liver repair by stimulating macrophage phenotype switching in the late phase of hepatic I/R injury., (Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Keywords: Carbohydrates; Chemical Biology; -Galactosylceramide; Glycolipids; iNKT Cells EN Carbohydrates Chemical Biology -Galactosylceramide Glycolipids iNKT Cells 1 1 1 07/18/22 20220714 NES 220714 B The Front Cover b illustrates the chemist's toolbox for the stimulation of invariant natural killer T cells with -galactosylceramide ( GalCer) and its derivatives. Front Cover: Chemical Biology of GalCer: A Chemist's Toolbox for the Stimulation of Invariant Natural Killer T (iNKT) Cells (Eur. J. Org. Carbohydrates, Chemical Biology, -Galactosylceramide, Glycolipids, iNKT Cells. [Extracted from the article]

Abstract: Mast cells play important roles via FcεRI-mediated activation in allergic asthma. A nonpolymorphic MHC I-like molecule CD1d, which is mainly expressed in APCs, presents glycolipid Ag to iTCR on iNKT cells and modulates allergic responses. This study aimed to investigate the role of CD1d on IgE production and mast cell activation related to allergic asthma. Bone marrow-derived mast cells (BMMCs) from C57BL/6 Wild type (WT) or KO (CD1d−/−) mice were activated with Ag/Ab (refer to WT-act-BMMCs and KO-act-BMMCs, respectively) or α-Galactosylceramide (WT-αGal-BMMCs, KO-αGal-BMMCs) in the presence of iNKT cells. WT, KO or BMMC-transferred KO mice were sensitized and/or challenged by OVA or α-Gal to induce asthma. KO-act-BMMCs reduced intracellular Ca2+ levels, expression of signaling molecules (Ras, Rac1/2, PLA2, COX-2, NF-κB/AP-1), mediator release (histamines, leukotrienes and cytokines/chemokines), and total IgE levels versus the corresponding WT-BMMCs. KO mice reduced total and OVA-specific serum IgE levels, number of mast cells, recruiting molecules (CCR2/CCL2, VCAM-1, PECAM-1), expression of tryptase, c-kit, CD40L and cytokine mRNA, co-localization of c-kit and CD1d or iNKT cells in BAL cells or lung tissues, and PCA responses, compared with the corresponding WT mice. BMMC-transferred KO-both mice showed the restoration of all allergic responses versus KO-both mice (Ag/Ab reaction plus α-Gal). KO-αGal-BMMCs or KO-αGal mice did not show any responses. Our data suggest that CD1d-expressed mast cells may function as APC cells for iNKT cells and exacerbate airway inflammation and remodeling through up-regulating IgE production via B cell Ig class switching and mediator release in mast cells of OVA-challenged mice. [Copyright &y& Elsevier]

Multiple sclerosis (MS) is an autoimmune disorder associated with neurological signs and chronic inflammatory demyelination of the central nervous system (CNS). MS has been thought as Th1 (T helper) and Th17 cells mediated disease, but cells of the innate immune system play an important role both in the initiation and progression of MS. The invariant Natural Killer T (iNKT) cells are the unique innate lymphocytes subtype involved in inflammation and autoimmune disorders and secretes cytokines such as interferon gamma (IFN-γ), Interleukin (IL)-10, IL-4 and IL-13. A reduction in number or defect in function of iNKT cells has been associated with an increased prevalence of autoimmune disorders indicating that iNKT cells have an immune-regulatory role in autoimmune disorders. Also, the protective role of iNKT cells has been extensively studied in EAE and the results of these studies show that iNKT cells might be a target for therapeutic purposes, but needs more extensive studies of their biology. In this review, we will attempt to show the protective role of iNKT cells in the pathogenesis of EAE and human disease. [ABSTRACT FROM AUTHOR]

Invariant Natural killer T cell (iNKT cells) are a subset of T cells, which are narrowly defined as a T cell lineage expressing a semi-invariant CD1d-restricted T cell Receptors (TCRs) composed by Vα24-Jα18/Vβ11 in human, and Vα14-Jα18/Vβ8,Vβ7, and Vβ2 in mouse. Unlike conventional T cells which recognize peptides bound to highly polymorphic major histocompatibility complex (MHC) class I and II molecules, iNKT cells recognize lipid antigens, such as glycolipids, presented by CD1d, a non-polymorphic non-classical MHC class I molecule. Lipids derived from microbes, tumors, and allergens, as well as self lipids have been shown to be able to activate iNKT cells. Early on, in an immune response, ligation of the iNKT cell TCR leads to rapid and copious secretion of prototypical Th1 and Th2 cytokines. Moreover, like NK cells, iNKT cells express cytotoxic granules, such as perforin and granzyme that polarize upon activation of TCR and are able to kill target cells. Therefore iNKT cells are a very interesting subset of T cells that may bridge the innate and adaptive immune systems. Indeed, iNKT cells can mount specific responses to antigen with cytokine production and cytotoxic activity, however, their TCR evolved to recognize different glycolipid antigens in a conserved manner and to perform innate-like rather than adaptive functions. iNKT cells are now recognized as important players in atopic, autoimmune, infectious diseases, and cancer. [ABSTRACT FROM AUTHOR]

Abstract: RCAI-147 is one of the hydroxylated analogues of KRN7000 which is known as a ligand for the activation of CD1d mediated invariant natural killer T cells (iNKT cells) and releases both T helper 1 (Th1) cytokines such as IFN-γ and T helper 2 (Th2) cytokines such as IL-4. KRN7000 has been anticipated as an antitumor drug or an adjuvant for viral infection such as influenza, because of its strong secretion of IFN-γ. In an interesting twist, it has been obvious in our previous paper that RCAI-147 induces much more Th2 cytokines (IL-4) than Th1 cytokines (IFN-γ) from iNKT cells compared to KRN7000, and shows fairly good result in the experimental autoimmune encephalomyelitis (EAE) test. Therefore, synthesis of RCAI-172 (C6-OH epimer of RCAI-147) was attempted to examine the biological activity. As a result, RCAI-172 was synthesized and its biological activity biased to Th2 response largely compared to that of KRN7000. However, this level decreased to approximately 61% compared to that of RCAI-147. And the clinical score of RCAI-172 for EAE suppression was disappointing. There exist seven chiral centers in the aglycon part of RCAI-172, and even though the change of configuration is just one position (C6-OH), the effect on both Th1/Th2 response and EAE test is fairly large. [Copyright &y& Elsevier]