Invariant natural killer <scp>T</scp> cells are not affected by lysosomal storage in patients with <scp>N</scp>iemann‐<scp>P</scp>ick disease type <scp>C</scp>

Speak, Anneliese O.; Platt, Nick; Salio, Mariolina; Vruchte, Daniëlle te; Smith, Dave; Shepherd, Dawn; Veerapen, Natacha; Besra, Gurdyal S.; Yanjanin, Nicole M.; Simmons, Louise; Imrie, Jackie; Wraith, J. E.; Lachmann, Robin; Hartung, Ralf; Runz, Heiko; Mengel, Eugen; Beck, Michael; Hendriksz, Christian J.; Porter, Forbes D.; Cerundolo, Vincenzo; Platt, Frances M.

doi:10.1002/eji.201141821

Cited by 14 publications

(19 citation statements)

References 27 publications

(35 reference statements)

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“…On the basis of the hypothesis that pAg þ stimulatory cells could be involved in transferring APC characteristics, we considered that although EBV-B cells are known to be capable of presenting antigen via MHC class I and II, their CD1d-restricted antigen-presenting capacities are compromised as EBV-B cells in vitro often downregulate CD1d expression on their cell surface and are thus relatively poor in presenting a-GalCer to iNKT cells (19,20). antigen CD19 could be observed (Fig.…”

Section: A-galcer-pulsed Pag-activated Vg9vd2-t Cells Do Not Trigger mentioning

confidence: 99%

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Schneiders¹,

Prodöhl²,

Ruben³

et al. 2014

Cancer Immunology Research

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CD1d-restricted invariant natural killer T cells (iNKT) constitute an important immunoregulatory T-cell subset that can be activated by the synthetic glycolipid a-galactosylceramide (a-GalCer) and play a dominant role in antitumor immunity. Clinical trials with a-GalCer-pulsed monocyte-derived dendritic cells (moDC) have shown anecdotal antitumor activity in advanced cancer. It was reported that phosphoantigen (pAg)-activated Vg9Vd2-T cells can acquire characteristics of professional antigen-presenting cells (APC). Considering the clinical immunotherapeutic applications, Vg9Vd2-T APC can offer important advantages over moDC, potentially constituting an attractive novel APC platform. Here, we demonstrate that Vg9Vd2-T APC can present antigens to iNKT. However, this does not result from de novo synthesis of CD1d by Vg9Vd2-T, but critically depends on trogocytosis of CD1d-containing membrane fragments from pAg-expressing cells. CD1d-expressing Vg9Vd2-T cells were able to activate iNKT in a CD1d-restricted and a-GalCer-dependent fashion. Although a-GalCerloaded moDC outperformed Vg9Vd2-T APC on a per cell basis, Vg9Vd2-T APC possess unique features with respect to clinical immunotherapeutic application that make them an interesting platform for consideration in future clinical trials. Cancer Immunol Res; 2(8); 732-40. Ó2014 AACR.

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Section: A-galcer-pulsed Pag-activated Vg9vd2-t Cells Do Not Trigger mentioning

confidence: 99%

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Schneiders¹,

Prodöhl²,

Ruben³

et al. 2014

Cancer Immunology Research

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“…Defects in iNKT cell populations have been reported in mouse models of lysosomal storage diseases (28,56,60), and it has been suggested that lysosomal storage per se may induce defects in mouse CD1d antigen presentation through spatial restrictions in the endocytic system and not necessarily because antigens are absent. However, this does not seem to be the case for human CD1d because iNKT cells levels are normal in Niemann-Pick disease type C and Fabry patients, which might be the result of the differences in intracellular trafficking of mouse and human CD1d molecules (61,62). LPLA2 is a lysosomal enzyme, and its absence induces phospholipidosis in alveolar and peritoneal macrophages (50); thus, reduced stimulation by Lpla2…”

Section: Discussionmentioning

confidence: 99%

Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition

Paduraru

Bezbradica

Kunte

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Invariant natural killer T (iNKT) cells recognize self lipid antigens presented by CD1d molecules. The nature of the self-antigens involved in the development and maturation of iNKT cells is poorly defined. Lysophospholipids are self-antigens presented by CD1d that are generated through the action of phospholipases A1 and A2. Lysosomal phospholipase A2 (LPLA2, group XV phospholipase A2) resides in the endocytic system, the main site where CD1d antigen acquisition occurs, suggesting that it could be particularly important in CD1d function. We find that Lpla2 −/− mice show a decrease in iNKT cell numbers that is neither the result of a general effect on the development of lymphocyte populations nor of effects on CD1d expression. However, endogenous lipid antigen presentation by CD1d is reduced in the absence of LPLA2. Our data suggest that LPLA2 plays a role in the generation of CD1d complexes with thymic lipids required for the normal selection and maturation of iNKT cells.antigen processing | lipid storage disease C D1d molecules are β 2 -microglobulin (β 2 m)-associated MHC class I homologs that bind lipid antigens and recycle between the plasma membrane and endocytic compartments. Endogenous and exogenous lipid binding can occur during transit through the secretory pathway and in the endocytic system, which is the main site of antigen loading (1). CD1d-lipid complexes are recognized by natural killer T (NKT) cells, a subset of T cells that shares characteristics of both the innate and adaptive arms of the immune system. NKT cells rapidly respond to stimulation by antigenpresenting cells (APCs) and release cytokines that can alter the strength and character of immune responses. They do so by transactivating, for example, NK cells, CD4+ and CD8 + T cells, and B cells, and by shifting cytokine responses to or from T helper (Th)1, Th2, and Th17 profiles. NKT cells have been shown to participate in inflammation, autoimmunity, cancer, and infectious diseases (2-4), and are characterized by the expression of both T-cell receptor (TCR) and NK cell markers. There are two main types: type I or invariant (iNKT), which express a semi-invariant TCR (Vα14-Jα18 in mice and Vα24-Jα18 in humans, paired with a restricted set of TCR-β chains, Vβ8.2, -7, or -2 in mice and Vβ11 in humans), and type II or noninvariant NKT cells that express more diverse TCRs (5-13).iNKT cells arise from double-positive (DP; CD4

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“…Earlier studies in Gaucher and Fabry disease patient, analyzed “iNKT-like” cells by the use of an antibody against Vα24 TCR α-chain, and no differences were observed between patients and controls [67,68,69]. Subsequent studies determined the frequency of iNKT cells in the peripheral blood of Fabry, Gaucher, and NPC disease patients, and no alterations in iNKT cell frequency were detected when compared with control subjects [13,70,71]. This can be attributed to the different trafficking pathways between human and mouse CD1d.…”

Section: Lysosomal Storage and Nkt Cellsmentioning

confidence: 99%

From Lysosomal Storage Diseases to NKT Cell Activation and Back

Pereira

Ribeiro

Macedo

2017

IJMS

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Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

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Invariant natural killer T cells are not affected by lysosomal storage in patients with Niemann‐Pick disease type C

Cited by 14 publications

References 27 publications

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Role for lysosomal phospholipase A2 in iNKT cell-mediated CD1d recognition

From Lysosomal Storage Diseases to NKT Cell Activation and Back

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