The current consensus on characterization of NKT cells is based on their reactivity to the synthetic glycolipid, a-galactosylceramide (a-GalCer) in a CD1d-dependent manner. Because of the limited availability of a-GalCer, there is a constant search for CD1d-presented ligands that activate NKT cells. The a-anomericity of the carbohydrate is considered to be an important requisite for the CD1d-specific activation of NKT cells. The gram-negative, lipopolysaccharide-free bacterium Sphingomonas paucimobilis is known to contain glycosphingolipids (GSL) with a-anomeric sugars attached to the lipid chain. Here, we report that GSL extracted from this bacterium are able to stimulate NKT cells in a CD1d-specific manner. In addition, soluble CD1d-Ig dimers loaded with this lipid extract specifically bind to NKT cells (but not conventional T cells). Further studies on the S. paucimobilis GSL could potentially lead to other natural sources of CD1d-specific ligands useful for NKT cell analyses and aimed at identifying novel therapies for a variety of disease states. IntroductionLipid antigens, including phospholipids and glycosphingolipids (GSL), are presented by CD1d -a subset of the CD1 family of MHC class I-like molecules -to specialized immune effector cells called NKT cells [1]. Located on a different chromosome than the MHC, five different CD1 genes encode CD1 molecules -CD1a, CD1b, CD1c, CD1d and CD1e -in humans, whereas only two homologues of CD1d (CD1d1 and CD1d2) are present in mice [2]. On the basis of the crystal structure of mouse CD1d1 [3], it is predicted that the fatty-acyl chains are buried in the hydrophobic pocket of the molecule with the hydrophilic head-group of the lipid antigen available outside the molecule for its interaction with the NKT cell receptor. Even though the lipidbinding groove of CD1d is widely accommodative of many lipid groups, it is believed that only the sugar structures in a-anomeric orientation are able to stimulate NKT cells [4]. Because of the lack of physiological glycolipids with terminal a-anomeric sugars, it is hypothesized that both altered selfglycolipids during a pathological process and exogenous antigenic glycolipids could be potential ligands presented by CD1d [4]. The presence of GSL in the cell wall of some bacterial strains indicates the possibility of these bacterial GSL being presented by CD1d. Although human CD1a, b and c molecules are known to present mycobacterial antigens to human NKT cells, there is a lack of substantial evidence to show that CD1d has the ability to present these microbial lipids [5]. In a recent study, Fischer et al. [6] were able to show that mycobacterial phosphoinositolmannosides (PIM) could bind to soluble CD1d and activate human and mouse NKT cells. However, only a fraction of NKT cells detected by agalactosylceramide (a-GalCer) could be stained by a CD1d tetramer loaded with mycobacterial PIM [6]. A recent study [7] was able to show the binding of synthetic a-GalNAc containing GSL to cell surface CD1d, but no functional studies were done t...

It is known that protein attachment to surfaces depends sensitively upon the local structure and environment of the binding sites at the nanometer scale. Using nanografting and reversal nanografting, both atomic force microscopy (AFM) - based lithography techniques, protein binding sites with well-defined local environments are designed and engineered with nanometer precision. Three proteins, goat-anti-biotin Immunoglobulin G (IgG), lysozyme and rabbit-Immunoglobulin G, are immobilized onto these engineered surfaces. Strong dependence on the dimension and spatial distribution of protein binding sites are revealed in antibody recognition, covalent attachment via primary amine residues and surface bound aldehyde-groups. This investigation indicates that AFM based nanolithography enables the production of protein nanostructures and more importantly, protein-surface interactions at a molecular level can be regulated by changing the binding domains and their local environment at nanometer scale.

IntroductionTumors must escape from the host's immune surveillance to survive and grow. Lymphoma is a general term for cancers that develop in the lymphatic system and it is the third most common cancer in children and adolescents. 1 To improve the outcome in patients with hematopoietic tumors, a better understanding of the immunobiology of lymphoma is essential. A novel lymphocyte population that has been identified as a key player in both innate and acquired immune responses, including as antitumor effector cells, is the natural killer T (NKT) cell. [2][3][4] NKT cells recognize lipid antigens presented by the MHC class I-like CD1d molecule and express cell surface markers shared with NK cells. 3 The vast majority of these T cells are canonical or invariant NKT (type I NKT) cells that possess a specific T-cell receptor (TCR) ␣-chain rearrangement (V␣14J␣18 in mice; V␣24J␣18 in humans), associated with V␤ chains of limited diversity. All other NKT cells that are CD1d-restricted and do not express this invariant TCR are called type II NKT cells. 5,6 Unlike type I NKT cells, little is known about type II NKT cells, but there is some evidence that type II NKT cells are a functionally important T-cell subset. 5 As CD1d molecules are vital for NKT-cell development, 7 mice lacking the CD1d1 gene (CD1KO mice) are deficient in all CD1d-restricted NKT cells (both type I and type II). 8 Mice lacking the J␣18 gene (J␣18KO mice) are deficient only in type I NKT cells. As NKT cells are capable of secreting both Th1 and Th2 cytokines, this has made it difficult to predict the consequences of their activation in vivo but has nonetheless created much speculation that they play a central role in immunoregulation. 2 NKT cells are directly cytotoxic and their activation can also result in "adjuvant effects" during antitumor immune responses by activating other cytotoxic lymphocytes, mainly through a Th1 cytokine cascade. 4 However, there are reports demonstrating a suppressive antitumor role for CD4 ϩ NKT cells in some murine tumor models, 9 and type II NKT cells were shown to be capable of down-regulating tumor immunosurveillance. 10 The role of NKT cells in the evasion of hematopoietic tumors from the host's innate antitumor immune response in vivo has only recently begun to be investigated, and we have reported that type I NKT cells play an inhibitory role in a murine T-cell lymphoma model. 11 Several human hematopoietic cell types express CD1d on their surface, 12 but the overall role of CD1d in antitumor immunity is not well understood. We have previously demonstrated that certain hematopoietic tumors shed glycolipids that mask CD1d-mediated antigen presentation to both type I and II NKT cells. 13 Recently, in vitro killing of EL-4 T-cell lymphoblastic lymphoma cells by type I NKT cells and their in vivo eradication in a CD1d-dependent manner has been reported. 14 CD11b and Gr-1 are the most common markers found on myeloid derived suppressor cells (MDSCs) and these cells are distinct from T lymphocytes and NK cells. 15 Accum...

A critical component of the host’s innate immune response involves lipid Ag presentation by CD1d molecules to NK T cells. In this study we used murine CD1d1-transfected L (L-CD1) cells to study the effect of viruses on CD1d-mediated Ag presentation to NKT cells and found that an infection with vesicular stomatitis and vaccinia (but not lymphocytic choriomeningitis) virus inhibited murine CD1d1-mediated Ag presentation. This was under the reciprocal control of the MAPKs, p38 and ERK, and was due to changes in the intracellular trafficking of CD1d1. The reciprocal regulation of CD1d1-mediated Ag presentation by MAPK suggests that the targeting of these pathways is a novel means of immune evasion by viruses.

Vinyl sulfones have long been known for their synthetic utility in organic chemistry, easily participating in 1,4-addition reactions and cycloaddition reactions. This functional group has also recently been shown to potently inhibit a variety of enzymatic processes providing unique properties for drug design and medicinal chemistry. This review includes traditional methods used for the synthesis of vinyl sulfones, but focuses mainly on newer reactions applied to vinyl sulfones, including olefin metathesis, conjugate reduction, asymmetric dihydroxylation (AD), and the use of vinyl sulfones to arrive at highly functionalized targets, all illustrating the rich and versatile chemistry this group can efficiently perform. In addition, geminal disulfones are discussed with respect to their formation, reactions, and medicinal applications of this underutilized functional group.