TCRβ Chain Influences But Does Not Solely Control Autoreactivity of Vα14J281T Cells

Gui, Ming; Li, Jin; Wen, Li; Hardy, Richard R.; Hayakawa, Kyoko

doi:10.4049/jimmunol.167.11.6239

Cited by 49 publications

(61 citation statements)

References 37 publications

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“…We also used b-GalCer at a 500 lg/ml concentration in these assays as a negative control. Differing only by the anomeric attachment of the sugar compared to aGalCer, as expected, b-GalCer was not presented to NKT cells [14,26,27] (data not shown). Fig.…”

Section: A-glcucer Is the Nkt Cell Activating Ligandsupporting

confidence: 60%

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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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Section: A-glcucer Is the Nkt Cell Activating Ligandsupporting

confidence: 60%

“…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]. The murine T cell hybridoma DO11.10 specific for ovalbumin was kindly provided by Dr J. Blum.…”

Section: Cell Lines and Other Reagentsmentioning

confidence: 99%

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

et al. 2005

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“…DN32.D3, a double-negative (CD4 À CD8 À ), Va14-Ja18 + mouse iNKT hybridoma cell line 14 was provided by Dr Albert Bendelac (The University of Chicago, Chicago, IL, USA). The CD4 + Va14 + mouse iNKT hybridoma cell lines N38-3C3 and N38-2C12 62 were generous gifts from Dr Kyoko Hayakawa (Fox Chase Cancer Centre, Philadelphia, PA, USA). All cell lines were grown in RPMI 1640 supplemented with 10% heat-inactivated fetal bovine serum, 0.1 mM minimal essential medium (MEM) non-essential amino acids, 2 mM L-glutamine, 1 mM sodium pyruvate, 100 U ml À1 penicillin, 100 mg ml À1 streptomycin and 50 mM 2-ME, which is referred to as complete medium in this article.…”

Section: Cell Linesmentioning

confidence: 99%

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

et al. 2011

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Invariant NKT (iNKT) cells are infrequent but important immunomodulatory lymphocytes that exhibit CD1d-restricted reactivity with glycolipid Ags. iNKT cells express a unique T-cell receptor (TCR) composed of an invariant a-chain, paired with a limited range of b-chains. Superantigens (SAgs) are microbial toxins defined by their ability to activate conventional T cells in a TCR b-chain variable domain (Vb)-specific manner. However, whether iNKT cells are directly activated by bacterial SAgs remains an open question. Herein, we explored the responsiveness of mouse and human iNKT cells to a panel of staphylococcal and streptococcal SAgs and examined the contribution of major histocompatibility complex (MHC) class II and CD1d to these responses. Bacterial SAgs that target mouse Vb8, such as staphylococcal enterotoxin B (SEB), were able to activate mouse hybridoma and primary hepatic iNKT cells in the presence of mouse APCs expressing human leukocyte antigen (HLA)-DR4. iNKT cell-mediated cytokine secretion in SEB-challenged HLA-DR4-transgenic mice was CD1d-independent and accompanied by a high interferon-c:interleukin-4 ratio consistent with an in vivo Th1 bias. Furthermore, iNKT cells from SEB-injected HLA-DR4-transgenic mice, and iNKT cells from SEB-treated human PBMCs, showed early activation by intracellular cytokine staining and CD69 expression. Unlike iNKT cell stimulation by a-galactosylceramide, stimulation by SEB did not induce TCR downregulation of either mouse or human iNKT cells. We conclude that Vb8-targeting bacterial SAgs can activate iNKT cells by utilizing a novel pathway that requires MHC class II interactions, but not CD1d. Therefore, iNKT cells fulfill important effector functions in response to bacterial SAgs and may provide attractive targets in the management of SAg-induced illnesses.

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“…N-butylgalactonojirimyin (NB-DGJ) was purchased from Calbiochem (EMD; San Diego, CA). The DN32.D3, N37-1A12, N38-2C12 and N38-3C3 mouse CD1d-specific hybridomas have been previously described [27][28][29] and were cultured in Iscove's modified Dulbecco's medium supplemented with 5% FBS and 2 mM L-glutamine. Purified and biotinylated monoclonal antibodies (mAb) specific for murine IL-2 were purchased from BD Pharmingen (San Diego, CA).…”

Section: Cell Lines and Other Reagentsmentioning

confidence: 99%

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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TCRβ Chain Influences But Does Not Solely Control Autoreactivity of Vα14J281T Cells

Cited by 49 publications

References 37 publications

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

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

CD1d‐independent activation of mouse and human iNKT cells by bacterial superantigens

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

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