Recycling CD1d1 Molecules Present Endogenous Antigens Processed in an Endocytic Compartment to NKT Cells

Roberts, Tonya; Sriram, Venkataraman; Spence, Philip M.; Gui, Ming; Hayakawa, Kyoko; Bačík, Igor; Bennink, Jack R.; Yewdell, Jonathan W.; Brutkiewicz, Randy R.

doi:10.4049/jimmunol.168.11.5409

Cited by 111 publications

(178 citation statements)

References 58 publications

Supporting

Mentioning

169

Contrasting

Unclassified

Order By: Relevance

“…These results are in accordance with those shown by Prigozy et al [16], and imply that GSL with more than one carbohydrate moiety attached to the ceramide bind to cell surface CD1d, but are endocytosed and processed to a simple GSL before being presented to NKT cells. The anti-mouse-CD1d monoclonal antibody 1H6 [17] (but not the negative control Ab) completely blocked the bacterial GSL presentation to NKT cells, confirming the CD1d-dependence of GSL recognition (Fig. 3).…”

Section: Resultssupporting

confidence: 59%

“…We have previously shown that the pharmacological inhibitors including chloroquine [18,19], primaquine, and bafilomycin A1 [20], that inhibit the endosomal recycling pathway and lysosomal enzyme activities by different modes of action, inhibit antigen-presentation by CD1d without altering its cell surface levels [1,17]. We thus assessed the requirement for intracellular processing of Sphingomonas GSL.…”

Section: Resultsmentioning

confidence: 99%

“…IL-2 release after 20 h of co-culture was measured by ELISA as described previously [17]. Where necessary, the target cells were also treated with the indicated concentrations of lysosomotropic agents (chloroquine and bafilomycin A1; Sigma-Aldrich, St. Louis, MO, USA), or an inhibitor of recycling (primaquine; SigmaAldrich), but the total lipid pulse time was maintained at 4 h. In some assays, the lipid-pulsed and drug-treated cells were fixed after the 4 h treatment period in 0.05% paraformaldehyde before being cocultured with NKT cells [17].…”

Section: Nkt Cell Stimulation Assaymentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Resultssupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Nkt Cell Stimulation Assaymentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…Further investigation will be required to determine the cause as well as the significance of this difference; however, we suspect it could be due to a differential effect of the MIR proteins on CD1d loading of endogenously versus exogenously derived antigens. CD1d molecules traffic extensively through the endocytic system (49)(50)(51)(52)(53) and are capable of presenting both exogenously derived (54) and endogenously derived antigens (46,55). However, it is not clear in which compartments the relevant physiological ligands of CD1d-restricted T cells are loaded, and it is possible that exogenous and endogenous cellular lipids may be loaded at different sites.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CD1d expression and function by a herpesvirus infection

Sanchez¹,

Gumperz²,

Ganem³

2005

J. Clin. Invest.

137

View full text Add to dashboard Cite

“…In order to determine the role of apoptosis in CD1d-mediated antigen presentation to NKT cells, murine LMTK fibroblasts transfected with the mouse cd1d1 cDNA (LMTK-CD1d1 cells) 26 were treated with various concentrations of the glycolipid biosynthesis inhibitors, PPMP, FB1 and NB-DGJ, and co-cultured with NKT cells. It is known that PPMP (but not FB1 or NB-DGJ) treatment results in an increased level of intracellular ceramide, leading to apoptosis, whereas FB1 inhibits the biosynthesis of the ceramide in the treated cells.…”

Section: Apoptosis Induction Inhibits Cd1d-mediated Antigen Presentationmentioning

confidence: 99%

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

et al. 2008

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Recycling CD1d1 Molecules Present Endogenous Antigens Processed in an Endocytic Compartment to NKT Cells

Cited by 111 publications

References 58 publications

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

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

Regulation of CD1d expression and function by a herpesvirus infection

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

Contact Info

Product

Resources

About