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 αβ TCRs recognize isoglobotrihexosylceramide, a mammalian glycosphingolipid, as well as microbial α-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.

The biology of NKT cells.

▪ Abstract This review summarizes the major features of CD1 genes and proteins, the patterns of intracellular trafficking of CD1 molecules, and how they sample different intracellular compartments for self- and foreign lipids. We describe how lipid antigens bind to CD1 molecules with their alkyl chains buried in hydrophobic pockets and expose their polar lipid headgroup whose fine structure is recognized by the TCR of CD1-restricted T cells. CD1-restricted T cells carry out effector, helper, and adjuvant-like functions and interact with other cell types including macrophages, dendritic cells, NK cells, T cells, and B cells, thereby contributing to both innate and adaptive immune responses. Insights gained from mice and humans now delineate the extensive range of diseases in which CD1-restricted T cells play important roles and reveal differences in the role of CD1a, CD1b, and CD1c in contrast to CD1d. Invariant TCRα chains, self-lipid reactivity, and rapid effector responses empower a subset of CD1d-restr...

CD1: antigen presentation and T cell function.

The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases.

Immunology in the liver — from homeostasis to disease

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.

Recognition of bacterial glycosphingolipids by natural killer T cells

The innate immune system provides many ways to quickly resist infection. The two best-studied defenses in dendritic cells (DCs) are the production of protective cytokines-like interleukin (IL)-12 and type I interferons-and the activation and expansion of innate lymphocytes. IL-12 and type I interferons influence distinct steps in the adaptive immune response of lymphocytes, including the polarization of T-helper type 1 (Th1) CD4+ T cells, the development of cytolytic T cells and memory, and the antibody response. DCs have many other innate features that do not by themselves provide innate resistance but are critical for the induction of adaptive immunity. We have emphasized three intricate and innate properties of DCs that account for their sentinel and sensor roles in the immune system: (1) special mechanisms for antigen capture and processing, (2) the capacity to migrate to defined sites in lymphoid organs, especially the T cell areas, to initiate immunity, and (3) their rapid differentiation or maturation in response to a variety of stimuli ranging from Toll-like receptor (TLR) ligands to many other nonmicrobial factors such as cytokines, innate lymphocytes, and immune complexes. The combination of innate defenses and innate physiological properties allows DCs to serve as a major link between innate and adaptive immunity. DCs and their subsets contribute to many subjects that are ripe for study including memory, B cell responses, mucosal immunity, tolerance, and vaccine design. DC biology should continue to be helpful in understanding pathogenesis and protection in the setting of prevalent clinical problems.

https://www.springer.com/cda/content/document/cda_downloaddocument/9783540326359-c1.pdf?SGWID=0-0-45-315593-p136755233

Dendritic Cells: Translating Innate to Adaptive Immunity

α-Galactosylceramide (α-GalCer) is a glycolipid that stimulates natural killer T cells to produce both T helper (Th) 1 and Th2 cytokines. This property enables α-GalCer to ameliorate a wide variety of infectious, neoplastic, and autoimmune diseases; however, its effectiveness against any one disease is limited by the opposing activities of the induced Th1 and Th2 cytokines. Here, we report that a synthetic C-glycoside analogue of α-GalCer, α-C-galactosylceramide (α-C-GalCer), acts as natural killer T cell ligand in vivo, and stimulates an enhanced Th1-type response in mice. In two disease models requiring Th1-type responses for control, namely malaria and melanoma metastases, α-C-GalCer exhibited a 1,000-fold more potent antimalaria activity and a 100-fold more potent antimetastatic activity than α-GalCer. Moreover, α-C-GalCer consistently stimulated prolonged production of the Th1 cytokines interferon-γ and interleukin (IL)-12, and decreased production of the Th2 cytokine IL-4 compared with α-GalCer. Finally, α-C-GalCer's enhanced therapeutic activity required the presence of IL-12, which was needed to stimulate natural killer cells for optimal interferon-γ production, but did not affect IL-4. Overall, our results suggest that α-C-GalCer may one day be an excellent therapeutic option for diseases resolved by Th1-type responses.

/pdf/superior-protection-against-malaria-and-melanoma-metastases-1z8ikz4dcx.pdf

Superior Protection against Malaria and Melanoma Metastases by a C-glycoside Analogue of the Natural Killer T Cell Ligand α-Galactosylceramide

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/anie.200454215

The C-Glycoside Analogue of the Immunostimulant α-Galactosylceramide (KRN7000): Synthesis and Striking Enhancement of Activity

Efficient Synthesis of α-C-Galactosyl Ceramide Immunostimulants: Use of Ethylene-Promoted Olefin Cross-Metathesis

Fifty-five retrieved tibial inserts with four different locking mechanisms were evaluated for evidence for polyethylene wear between the inferior surface of the tibial insert and metal tray. This type of wear will be referred to as backside wear. Backside wear was assessed by evaluating manufacturer's stamped markings on the inferior polyethylene surface. Because these markings are embossed into the polyethylene surface, they were used as indicators of backside wear. Decreases in the depths of markings indicated that backside wear was clearly evident, regardless of design, in 24 (44%) of the inserts. In eight of these 24 inserts, the manufacturer's stamped markings were removed completely. The amount of polyethylene wear was as a high as 591 mg from the inferior surface. This corresponds to a polyethylene wear rate from the backside of the tibial insert of greater than 100 mg per year, which is two to four times higher than wear rates associated with total hip replacements. The current work provides direct evidence of backside wear in all four tibial insert designs. Backside wear of tibial inserts can be a significant contributor to polyethylene wear in total knee arthroplasty. Close attention should be given to the fixation of tibial inserts to metal trays by manufacturers and surgeons.

Assessment of backside wear from the analysis of 55 retrieved tibial inserts.

Cell-mediated immunity plays a crucial role in the control of many infectious diseases, necessitating the need for adjuvants that can augment cellular immune responses elicited by vaccines. It is well established that protection against one such disease, malaria, requires strong CD8+ T cell responses targeted against the liver stages of the causative agent, Plasmodium spp. In this report we show that the dendritic cell-specific chemokine, dendritic cell-derived CC chemokine 1 (DC-CK1), which is produced in humans and acts on naive lymphocytes, can enhance Ag-specific CD8+ T cell responses when coadministered with either irradiated Plasmodium yoelii sporozoites or a recombinant adenovirus expressing the P. yoelii circumsporozoite protein in mice. We further show that these enhanced T cell responses result in increased protection to malaria in immunized mice challenged with live P. yoelii sporozoites, revealing an adjuvant activity for DC-CK1. DC-CK1 appears to act preferentially on naive mouse lymphocytes, and its adjuvant effect requires IL-12, but not IFN-γ or CD40. Overall, our results show for the first time an in vivo role for DC-CK1 in the establishment of primary T cell responses and indicate the potential of this chemokine as an adjuvant for vaccines against malaria as well as other diseases in which cellular immune responses are important.

The Dendritic Cell-Specific Chemokine, Dendritic Cell-Derived CC Chemokine 1, Enhances Protective Cell-Mediated Immunity to Murine Malaria

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