Lipid-Antigen Presentation by CD1d B Cells Is Essential for the Maintenance of Invariant Natural Killer T Cells

Centre for Rheumatology Research, Division of Medicine, University College London, London WC1E 6JF, UK.
Immunity (Impact Factor: 21.56). 03/2012; 36(3):477-90. DOI: 10.1016/j.immuni.2012.02.008
Source: PubMed


B cells perform many immunological functions, including presenting lipid antigen to CD1d-restricted invariant natural killer T (iNKT) cells, known to contribute to maintaining tolerance in autoimmunity. Patients with systemic lupus erythematous (SLE) display dysregulated B cell responses and reduced peripheral iNKT cell frequencies. The significance of these defects and how they relate to SLE pathogenesis remain elusive. We report that B cells are essential for iNKT cell expansion and activation in healthy donors but fail to exert a similar effect in SLE patients. Defective B cell-mediated stimulation of iNKT cells in SLE patients was associated with altered CD1d recycling, a defect recapitulated in B cells from healthy donors after stimulation with interferon-α (IFN-α) and anti-immunoglobulin (Ig). iNKT cell number and function were restored in SLE patients responding to anti-CD20 treatment upon normalization of CD1d expression exclusively in repopulated immature B cells. We propose that healthy B cells are pivotal for iNKT cell homeostasis.

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Available from: Anneleen Bosma, Sep 30, 2015
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    • "However, Yan-Ming et al. reported that IL-10 production from iNKT cells was reduced in asthma patients.17 Bosma et al. determined the frequency of blood IL-10-producing iNKT cells from patients with systemic lupus erythematosus and found the frequency was increased compared to controls.20 Although the role of IL-10-producing iNKT cells in asthma is not known, they might play a regulatory role in asthma pathogenesis, similar to regulatory T cells in asthma and allergic diseases. "
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    ABSTRACT: Purpose Invariant natural killer T (iNKT) cells might play an important role in asthma pathogenesis in humans. Our previous study found no difference in the number of blood iNKT cells between asthma patients and controls. However, few studies have examined the function of blood iNKT cells in human asthma. Methods Twenty asthma patients and eight controls were included in this study. Blood iNKT cells were identified using double staining with anti-Vα24 and anti-Vβ11 monoclonal antibodies (mAbs) or with 6B11 and anti-Vβ11 mAbs. Intracellular IL-4, IL-10, and IFN-γ cytokines were stained in blood iNKT cells using their respective mAbs and isotypes. In addition, their relationships with clinical parameters were analyzed. Results The number of Vα24+Vβ11+ iNKT cells or 6B11+Vβ11+ iNKT cells did not differ between asthma patients and controls. However, among Vα24+Vβ11+iNKT cells, the proportion of IL-4+iNKT cells was increased in asthma patients compared to controls (7.0±3.0% vs 0.5%±0.4%, P<0.05). There were no differences in the proportions of IL-10+or IFN-γ+iNKT cells between the groups. The proportion of IL-4+ cells among 6B11+Vβ11+iNKT cells inversely correlated with FEV1, expressed as a percentage predicted value in asthma patients (Rs=-0.64, P<0.05, n=19). Conclusions Blood iNKT cells are thought to be Th2-like, and IL-4-producing iNKT cells may be associated with lung function in human asthma.
    Allergy, asthma & immunology research 09/2014; 6(5):444-8. DOI:10.4168/aair.2014.6.5.444 · 2.43 Impact Factor
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    • "High levels of CD1d expression result in higher tumor cell death, whereas low levels of CD1d expression result in minimal tumor cell lysis [44,45]. In addition, specific subsets of human B cells have been reported to express CD1d [46–48]. Therefore, we next examined CD1d expression on human B cell lymphoma cell lines (Figure 2A). "
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    ABSTRACT: Natural killer T (NKT) cells are a unique subset of CD1d-restricted T lymphocytes that express characteristics of both T cells and natural killer cells. NKT cells mediate tumor immune-surveillance; however, NKT cells are numerically reduced and functionally impaired in lymphoma patients. Many hematologic malignancies express CD1d molecules and co-stimulatory proteins needed to induce anti-tumor immunity by NKT cells, yet most tumors are poorly immunogenic. In this study, we sought to investigate NKT cell responses to B cell lymphoma. In the presence of exogenous antigen, both mouse and human NKT cell lines produce cytokines following stimulation by B cell lymphoma lines. NKT cell populations were examined ex vivo in mouse models of spontaneous B cell lymphoma, and it was found that during early stages, NKT cell responses were enhanced in lymphoma-bearing animals compared to disease-free animals. In contrast, in lymphoma-bearing animals with splenomegaly and lymphadenopathy, NKT cells were functionally impaired. In a mouse model of blastoid variant mantle cell lymphoma, treatment of tumor-bearing mice with a potent NKT cell agonist, α-galactosylceramide (α-GalCer), resulted in a significant decrease in disease pathology. Ex vivo studies demonstrated that NKT cells from α-GalCer treated mice produced IFN-γ following α-GalCer restimulation, unlike NKT cells from vehicle-control treated mice. These data demonstrate an important role for NKT cells in the immune response to an aggressive hematologic malignancy like mantle cell lymphoma.
    06/2014; 2(2):82-97. DOI:10.3390/medsci2020082
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    • "(iNKT) cells [24], we focused our studies on this molecule, which is also the only CD1 isoform expressed by mouse [7] [25]. Two isoforms of CD1d have been observed on the surface of cells: one that is physically bound to β2-microglobulin (β 2 m) and the other that is independently present without β 2 m [11] [26]. "
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    ABSTRACT: Cluster of differentiation 1 (CD1) represents a family of proteins which is involved in lipid-based antigen presentation. Primarily, antigen presenting cells, like B cells, express CD1 proteins. Here, we examined the cell-surface distribution of CD1d, a subtype of CD1 receptors, on B lymphocytes. Fluorescence labeling methods, including fluorescence resonance energy transfer (FRET),were employed to investigate plasma membrane features of CD1d receptors. High FRET efficiency was observed between CD1d and MHC I heavy chain (MHC I-HC), β2-microglobulin(β2m) and MHC II proteins in the plasma membrane. In addition, overexpression of CD1d reduced the expression of MHC II and increased the expression of MHC I-HC and β2m proteins on the cell-surface. Surprisingly, β2m dependent CD1d isoform constituted only ~15% of the total membrane CD1d proteins. Treatment of B cells with methyl-β-cyclodextrin (MβCD) / simvastatin caused protein rearrangement; however, FRET demonstrated only minimal effect of these chemicals on the association between CD1d and GM1 ganglioside on cell-surface.Likewise, a modest effect was only observed in a co-culture assay between MβCD/simvastatin treated C1R–CD1d cells and invariant natural killer T cells on measuring secreted cytokines (IFNγ and IL4). Furthermore,CD1d rich regions were highly sensitive to low concentration of Triton X-100. Physical proximity between CD1d, MHC and GM1 molecules was also detected in the plasma membrane. An intricate relationship between CD1d, MHC, and lipid species was found on the membrane of human B cells. Organization of CD1d on the plasma membrane might be critical for its biological functions.
    Biochimica et Biophysica Acta 01/2014; 1840(1):667-80. DOI:10.1016/j.bbagen.2013.10.030 · 4.66 Impact Factor
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