Lysosomal Glycosphingolipid Recognition by NKT Cells

Zhou, Dapeng; Mattner, Jochen; Cantu, Carlos; Schrantz, Nicolas; Yin, Ning; Gao, Ying; Sagiv, Yuval; Hudspeth, Kelly; Wu, Yun Ping; Yamashita, Tadashi; Teneberg, Susann; Wang, Dacheng; Proia, Richard L.; Levery, Steven B.; Savage, Paul B.; Teyton, Luc; Bendelac, Albert

doi:10.1126/science.1103440

Cited by 885 publications

(927 citation statements)

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“…[31] and phosphoethanolamine [32] have recently been identified as ligands for iNKT cells, although all of these activate iNKT cells to a lesser degree than a-GalCer. Although lysosomal glycosphingolipid, isoglobotrihexosylceramide has been reported as a possible endogenous ligand for iNKT cells [28,33], a recent study argues against this possibility [34]. iNKT cells are abundant in the liver and rapidly secrete large amounts of immunoregulatory cytokines such as IFN-g and IL-4 after stimulation through their TCR [35][36][37][38][39][40].…”

Section: Introductionmentioning

confidence: 99%

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Emoto

Yoshizawa

et al. 2010

Eur J Immunol

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a-Galactosylceramide (a-GalCer) activates invariant (i)NKT cells, which in turn stimulate immunocompetent cells. Although activation of iNKT cells appears critical for regulation of immune responses, it remains elusive whether protection against intracellular bacteria can be induced by a-GalCer. Here, we show that a-GalCer treatment ameliorates murine listeriosis, and inhibits inflammation following Listeria monocytogenes infection. Liver infiltration of Gr-1 1 cells and c/d T cells was accelerated by a-GalCer treatment. Gr-1 1 cell and c/d T-cell depletion exacerbated listeriosis in a-GalCer-treated mice, and this effect was more pronounced after depletion of Gr-1 1 cells than that of c/d T cells. Although GM-CSF and IL-17 were secreted by NKT cells after a-GalCer treatment, liver infiltration of Gr-1 1 cells was not prevented by neutralizing mAb. In parallel to the numerical increase of CD11b 1 Gr-1 1 cells in the liver following a-GalCer treatment, CD11b À Gr-1 1 cells were numerically reduced in the bone marrow. In addition, respiratory burst in Gr-1 1 cells was enhanced by a-GalCer treatment. Our results indicate that a-GalCer-induced antibacterial immunity is caused, in part, by accelerated infiltration of Gr-1 1 cells and to a lesser degree of c/d T cells into the liver. We also suggest that the infiltration of Gr-1 1 cells is caused by an accelerated supply from the bone marrow.Key words: a-galactosylceramide . L. monocytogenes . NKT cell Supporting Information available online IntroductionListeria monocytogenes is a Gram-positive facultative intracellular bacterial pathogen, which causes disseminated infection in immunocompromised hosts [1]. Experimental murine listeriosis is instrumental in elucidating host defense mechanisms against intracellular bacteria. Cells of the innate immune system play a pivotal role as a first line of defense against L. monocytogenes [2-5] and among these, Gr-1 1 cells are central for the elimination of this pathogen at early stages of infection [6][7][8]. Numerous cytokines such as GM-CSF, IL-3, IL-6, IL-11, and SCF promote granulopoiesis by themselves and/or in concert with G-CSF [9,10]. G-CSF is indispensable for both steady-state and emergency granulopoiesis [11][12][13][14], and IL-17 regulates G-CSF secretion [9,10,[15][16][17][18]. In addition to Gr-1 1 cells, g/d T cells also participate in early protection against 1328L. monocytogenes infection [19][20][21][22]. The vast majority of L. monocytogenes organisms are trapped in the liver immediately after systemic infection [23] and hence, immunocompetent cells that reside in, and/or migrate into, the liver are critical for infection control.NKT cells represent a unique subset of T lymphocytes, which are characterized by the co-expression of NK cell markers such as NKR-P1B/C (NK1.1; CD161) [24]. In the mouse, the majority of NKT cells express an invariant (i) TCR composed of Va14/Ja18 gene segments, i.e. iNKT cells [24]. In contrast to conventional T cells, which recognize peptide antigens presented by polymorphic MHC ...

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Section: Introductionmentioning

confidence: 99%

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Emoto

Yoshizawa

et al. 2010

Eur J Immunol

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“…GM1/GA1 can no longer be degraded to GM2/GA2 and GM3/GA3 and represent the most prominent glycolipids accumulating in patients and mice deficient in bGal [44][45][46]. However, the lack of gangliosides such as GM2/GA2 or GM3/GA3 probably does not explain deficient development of Va14i NKT cells in bGal -/-mice since mice lacking ganglio-series glycolipids as a result of genetic deficiency of GM2 or GM3 synthase, i.e., the key enzymes for their synthesis, displayed no apparent defect in development of Va14i NKT cells [28]. Lactosylceramide does not accumulate in bGal -/-mice because its degradation, involving the removal of terminal b-galactose residues, can be exerted by an alternative enzyme, galactosylceramidase (EC 3.2.1.46) [47,48].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, mouse models of lipid storage diseases have been studied with respect to the relevance of lysosomal enzymes and lipid transfer proteins for stimulation and selection of a specialized population of T cells, i.e., Va14i NKT cells, recognizing glycolipid antigens in the context of CD1d antigen-presenting molecules. These studies revealed that Hexb- [28,32], Hexa- [32], aGal- [32], bGal- [32], saposin- [29], or NPC1- [31,32] deficient mice have reduced numbers of Va14i NKT cells and, in the cases of Hexb -/-, bGal -/-, saposin -/-, and NPC1 -/-mice, defects in lipid antigen presentation. Va14i NKT cell deficiency has originally been explained as a result of lacking iGb3 in the case of Hexb -/-, and of impaired saposin-mediated lipid transfer onto CD1d molecules in the case of saposin -/-mice.…”

Section: Discussionmentioning

confidence: 99%

“…Recent work suggested that isoglobotrihexosylceramide (iGb3), a lysosomal glycosphingolipid that is absent in mice deficient in b-hexosaminidases A and B (Hexb -/-), is involved in thymic selection of Va14i NKT cells [28]. Furthermore, different lysosomal lipid transfer proteins, i.e., saposins and GM2 activator protein, have been implicated in loading of endogenous and exogenous lipid antigens onto CD1d and thus in CD1d-restricted presentation of selection-relevant lipid antigens to Va14i NKT cells [29,30].…”

Section: Introductionmentioning

confidence: 99%

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Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism

et al. 2007

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Deficiencies in enzymes of the lysosomal glycosphingolipid degradation pathway or in lysosomal lipid transfer proteins cause an imbalance in lipid metabolism and induce accumulation of certain lipids. A possible impact of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells has only been hypothesized but not extensively studied so far. Here we demonstrate that presentation of lipid antigens to, and development of, lipid-reactive CD1d-restricted NKT cells, are impaired in mice deficient in the lysosomal enzyme b-galactosidase (bGal) or the lysosomal lipid transfer protein Niemann-Pick C (NPC) 2. Importantly, the residual populations of NKT cells selected in bGal -/-and NPC2 -/-mice showed differential TCR and CD4 repertoire characteristics, suggesting that differential selecting CD1d:lipid antigen complexes are formed. Furthermore, we provide direct evidence that accumulation of lipids impairs lipid antigen presentation in both cases. However, the mechanisms by which imbalanced lipid metabolism affected lipid antigen presentation were different. Based on these results, the impact of lipid accumulation should be generally considered in the interpretation of immunological deficiencies found in mice suffering from lipid metabolic disorders.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37160_s.pdf IntroductionDefects in lysosomal lipid trafficking or degradation result in a severe imbalance of lipid metabolism. Little is known about the consequences of such an imbalance on the presentation of lipid antigens to lipid-reactive T cells, e.g., the important immunoregulatory invariant (i) NKT cell subset (Va14i and Va24i NKT cells in mice and humans, respectively), which recognizes glycolipid antigens presented by the MHC class I-like molecule Abbreviations: a-GalCer: a-galactosylceramide (KRN7000) Á a/bGal: a/b-galactosidase Á DN: CD4 -CD8 -double negative Á DP: CD4 + CD8 + double positive Á Hex: hexosaminidase Á HSA: heat-stable Ag Á i: invariant Á iGb3: isoglobotrihexosylceramide Á NB-DNJ: N-butyldeoxynojirimycin Á NPC: NiemannPick C Eur. J. Immunol. 2007Immunol. . 37: 1431Immunol. -1441 CD1d. In mice, the TCR of Va14i NKT cells is composed of an invariant Va14-Ja18 chain, paired preferentially with a restricted b chain, mostly containing Vb8.2 or Vb7 (the human equivalents are Va24-Ja18 and Vb11) [1][2][3][4]. Va14i NKT cells are implicated in the regulation of antitumor immunity, antimicrobial responses, and the balance between tolerance and autoimmunity [5,6]. Va14i NKT cells, which can be either CD4 + or CD4 -CD8 -double negative (DN), are a thymus-dependent population derived from CD4 + CD8 + double-positive (DP) thymocytes [7][8][9][10][11]. Different maturation stages of developing thymic Va14i NKT cells have been described, characterized by the sequential acquisition of CD44 and NK1.1 in C57BL/6 mice [12][13][14]. Unlike conventional MHC-dependent T cells, Va14i NKT cells are not positively selected by thymic epithelial cell...

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“…When the lysosomal glycosphingolipid (GSL) isoglobotrihexosylceramide (iGb3) was described as an endogenous, and perhaps the selecting, ligand for iNKT cells [66], it faced a good deal of skepticism, mainly because humans are believed to lack functional α1,3 Galactosyltransferase [67,68], an enzyme thought to be critical to the synthesis of iGb3. Two papers published last year raised some doubts regarding the role of iGb3 as a self-antigen.…”

Section: Endogenous Inkt Cell Antigensmentioning

confidence: 99%

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

Matsuda

Mallevaey

Scott‐Browne

et al. 2008

Current Opinion in Immunology

359

399

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SummaryNatural Killer T cells are a distinct lymphocyte lineage that regulates a broad range of immune responses. NKT cells recognize glycolipids presented by the non-classical MHC molecule CD1d. Structural insight into the TCR/glycolipid/CD1d tri-complex has revealed an unusual and unexpected mode of recognition. Recent studies have also identified some of the signaling events during NKT cell development that give NKT cells their innate phenotype. Pathogen-derived glycolipid antigens continue to be found, and new mechanisms of NKT cell activation have been described. Finally, NKT cells have been shown to be remarkably versatile in function during various immune responses. Whether these extensive functional capacities can be attributed to a single population sensitive to environmental cues or if functionally distinct NKT cell subpopulations exist remains unresolved.

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Lysosomal Glycosphingolipid Recognition by NKT Cells

Cited by 885 publications

References 31 publications

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

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Lysosomal Glycosphingolipid Recognition by NKT Cells

Cited by 885 publications

References 31 publications

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1+ cells into the liver

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1+ cells into the liver

Differential alteration of lipid antigen presentation to NKT cells due to imbalances in lipid metabolism

CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system

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Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1⁺ cells into the liver