A biased Vα24+ T-cell repertoire leads to circulating NKT-cell defects in a multiple sclerosis patient at the onset of his disease

Démoulins, Thomas; Gachelin, Gabriel; Béquet, D.; Dormont, Dominique

doi:10.1016/j.imlet.2003.09.014

Cited by 38 publications

(26 citation statements)

References 31 publications

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“…Similarly, deficiencies in peripheral blood NKT cell numbers, or IL-4 secretion by NKT cells, have been reported in patients with remitting-relapsing multiple sclerosis (73)(74)(75)(76)(77). Again, a few groups have disputed these findings, with one reporting no clear association (74) and another claiming NKT cell numbers are increased (78).…”

Section: Discussionmentioning

confidence: 99%

Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice

Jordan

Fletcher

Jose

et al. 2011

The Journal of Immunology

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Allelic variation of SLAM expression on CD4+CD8+ thymocytes has been proposed to play a major role in NKT cell development. In this article, this hypothesis is tested by the production of subcongenic mouse strains and Slamf1 transgenic lines. The long isoform of the C57BL/6 allele of Slamf1 was transgenically expressed on CD4+CD8+ thymocytes under control of an hCD2 minigene. NOD.Nkrp1b.Tg(Slamf1)1 mice, which had a 2-fold increase in SLAM protein expression on CD4+CD8+ thymocytes, had a 2-fold increase in numbers of thymic NKT cells. The additional thymic NKT cells in NOD.Nkrp1b.Tg(Slamf1)1 mice were relatively immature, with a similar subset distribution to those of congenic NOD.Nkrp1b.Nkt1 and NOD.Nkrp1b.Slamf1 mice, which also express increased levels of SLAM on CD4+CD8+ thymocytes and produce larger numbers of NKT cells. Transgenic enhancement of SLAM expression also increased IL-4 and IL-17 production in response to TCR-mediated stimulation. Paradoxically, NOD.Nkrp1b.Tg(Slamf1)2 mice, which had a 7-fold increase in SLAM expression, showed no significant increase in NKT cells numbers; on the contrary, at high transgene copy number, SLAM expression levels correlated inversely with NKT cell numbers, consistent with a contribution to negative selection. These data confirm a role for SLAM in controlling NKT cell development and are consistent with a role in both positive and negative thymic selection of NKT cells.

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Section: Discussionmentioning

confidence: 99%

Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice

Jordan

Fletcher

Jose

et al. 2011

The Journal of Immunology

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“…A decrease in Vα24 mRNA was demonstrated in peripheral blood of MS patients [96] that seemed to coincide with the relapse state of the disease [97]. Additionally, the IL-4 secretion of DN NKT cells was reduced [98].…”

Section: Experimental Autoimmune Encephalomyelitis and Multiple Sclermentioning

confidence: 95%

Immunoregulation of Autoimmunity by Natural Killer T Cells

2005

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“…The inflammatory process is triggered by T cells reacting with myelin antigens. Several studies have provided evidence that the prevalence of NKT cells in peripheral blood of MS patients is reduced [95,96] and this seemed to coincide with the relapse state of the disease [97]. In addition, double negative NKT cells in these patients exhibited a defect in IL-4 production [98].…”

Section: Multiple Sclerosis and Its Animal Mo-delsmentioning

confidence: 99%

Natural Killer T Cells and Autoimmune Disease

Kaer²

2009

CMM

158

159

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Natural killer T (NKT) cells are an unusual subset of innate immune cells that express a surface receptor generated by somatic DNA rearrangement, a hallmark of cells of the adaptive immune system. NKT cells express a highly restricted repertoire of T cell receptors that recognize glycolipid antigens bound with the antigen-presenting molecule CD1d. A hallmark of NKT cells is their capacity to produce copious amounts of immunomodulatory cytokines upon antigenic stimulation, which endows these cells with potent immunoregulatory properties. Consequently, NKT cells have been implicated in regulating a wide variety of immune responses, including immune responses against autoantigens. In patients and mice with a variety of autoimmune diseases, numbers and functions of NKT cells are disturbed, but the relevance of these findings to the etiology of autoimmunity remains to be fully established. Nevertheless, in some mouse models of autoimmunity, NKT cell-deficiency exacerbates disease, suggesting that NKT cells play a role in suppressing autoimmunity. Conversely, specific activation of NKT cells with glycolipid antigens generally protects mice against the development of autoimmunity. Most of these studies have employed the potent sponge-derived NKT cell antigen alpha-galactosylceramide (alpha-GalCer). However, alpha-GalCer treatment in mice was associated with detrimental side effects and treatment efficacy was influenced by a variety of parameters, resulting sometimes in disease exacerbation rather than protection. Recent efforts have focused on developing NKT cell agonists with superior treatment efficacy than alpha-GalCer. Collectively, these studies have identified NKT cells as attractive targets for treatment of human autoimmune diseases.

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A biased Vα24+ T-cell repertoire leads to circulating NKT-cell defects in a multiple sclerosis patient at the onset of his disease

Cited by 38 publications

References 31 publications

Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice

Role of SLAM in NKT Cell Development Revealed by Transgenic Complementation in NOD Mice

Immunoregulation of Autoimmunity by Natural Killer T Cells

Natural Killer T Cells and Autoimmune Disease

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