Inhibition of glycolipid shedding rescues recognition of a CD1<sup>+</sup>T cell lymphoma by natural killer T (NKT) cells

Sriram, Venkataraman; Cho, Sungyoo; Li, Ping; O’Donnell, Patrick W.; Dunn, Claire; Hayakawa, Kyoko; Blum, Janice S.; Brutkiewicz, Randy R.

doi:10.1073/pnas.122636199

Cited by 81 publications

(86 citation statements)

References 43 publications

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“…If ceramide was able to inhibit the generation or availability of a non-ceramide-based ligand, one would predict it would affect antigen presentation to either a canonical or non-canonical NKT cell (but not both), as previous data by us suggest that the Va5 + N37-1A12 NKT cell hybridoma can recognize a ligand(s) distinct from those 'seen' by canonical NKT cells (ref. 53 and Fig. 4f in the current manuscript).…”

Section: Discussionmentioning

confidence: 67%

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

et al. 2008

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SummaryThe stimulation of programmed cell death can either enhance or inhibit antigen presentation by classic major histocompatibility complex molecules. In the current study, we report that the induction of apoptosis by topoisomerase I inhibition or elevation of intracellular ceramide levels substantially impairs CD1d-mediated antigen presentation. In the former case, such a reduction occurred via the regulation of both the p38 mitogen-activated protein kinases and protein kinase C d signal transduction pathways as well as the caspase cascade, whereas the latter was p38-(but not caspase)-dependent. Confocal microscopic analysis showed an altered intracellular distribution of CD1d following the inhibition topoisomerase I or by an increase in intracellular ceramide levels, that was prevented by p38 and caspase inhibitors. Thus, the induction of apoptosis in antigen presenting cells severely compromises CD1d-mediated antigen presentation by multiple mechanisms.

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Section: Discussionmentioning

confidence: 67%

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

et al. 2008

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“…It has recently been shown that this reactivity to self antigens can be exploited in a novel activation strategy that may allow for the rapid triggering of CD1d-restricted T cells in a wide variety of pathogenic infections (9). However, other lipids derived from tumors may be inhibitory in nature, which suggests multiple systems of control within the CD1d-restricted T cell system (47). Under normal circumstances, CD1d-restricted T cell recognition of self antigens results in little cytokine secretion; however, in the presence of the cytokines IL-12 and IL-2, which are produced by APCs in response to microbial products, the effect of self-antigen recognition is amplified, leading to potent IFN-γ production by CD1d-restricted T cells.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CD1d expression and function by a herpesvirus infection

Sanchez¹,

Gumperz²,

Ganem³

2005

J. Clin. Invest.

137

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“…Murine LMTK fibroblasts transfected with either the empty vector pCDNA3.1 (-) (LMTK-vector) or vector containing cd1d1 cDNA (LMTK-CD1d1WT) were cultured and used as described previously [44]. The CD1d1-specific murine NKT cell hybridomas DN32.D3 (Va14 + ) [45], N37-1A12 (Va5 + ), and the a-GalCer-dependent N38-2C12 (Va14 + ), N38-3C3 (Va14 + ) NKT cell hybridomas have been described [14,27].…”

Section: Cell Lines and Other Reagentsmentioning

confidence: 99%

“…LMTKvector or LMTK-CD1d1WT cells were treated with either vehicle or lipids for 4 h at 37 C, and washed extensively before culture with NKT cell hybridomas [44]. IL-2 release after 20 h of co-culture was measured by ELISA as described previously [17].…”

Section: Nkt Cell Stimulation Assaymentioning

confidence: 99%

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

et al. 2005

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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...

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Inhibition of glycolipid shedding rescues recognition of a CD1⁺T cell lymphoma by natural killer T (NKT) cells

Cited by 81 publications

References 43 publications

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

Regulation of CD1d expression and function by a herpesvirus infection

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

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Inhibition of glycolipid shedding rescues recognition of a CD1+T cell lymphoma by natural killer T (NKT) cells

Cited by 81 publications

References 43 publications

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

Apoptosis‐induced inhibition of CD1d‐mediated antigen presentation: different roles for caspases and signal transduction pathways

Regulation of CD1d expression and function by a herpesvirus infection

Cell wall glycosphingolipids ofSphingomonas paucimobilisare CD1d-specific ligands for NKT cells

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Inhibition of glycolipid shedding rescues recognition of a CD1⁺T cell lymphoma by natural killer T (NKT) cells