NK T Cell-Induced Protection Against Diabetes in Vα14-Jα281 Transgenic Nonobese Diabetic Mice Is Associated with a Th2 Shift Circumscribed Regionally to the Islets and Functionally to Islet Autoantigen

Laloux, Véronique; Beaudoin, Lucie; Jeske, Dirk; Carnaud, Claude; Lehuen, Agnès

doi:10.4049/jimmunol.166.6.3749

Cited by 109 publications

(85 citation statements)

References 44 publications

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“…In concordance, upregulation of CD1d expression restored the immunoregulatory function of NKT cells and prevented autoimmune diabetes [74]. Protection conferred by NKT cells was associated with a Th2 shift within the pancreatic islets, and IL-4 has been implicated as a key mediator of immunoregulation [69,75]. Stimulation of naïve T cells expressing a transgenic, diabetogenic TCR with their auto-antigen in the presence of NKT cells did not block the initial activation of the pathogenic T cells.…”

Section: Type 1 Diabetesmentioning

confidence: 57%

Immunoregulation of Autoimmunity by Natural Killer T Cells

2005

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Section: Type 1 Diabetesmentioning

confidence: 57%

Immunoregulation of Autoimmunity by Natural Killer T Cells

2005

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“…A similar protection was observed after specific iNKT cell stimulation with exogenous ligands, a-galactosylceramide (a-GalCer) and its analogues [8][9][10][11]. Early reports suggested that iNKT cell protection was associated with the induction of a Th2 response to islet autoantigens [8,[10][11][12]. However, following studies using the transfer of anti-islet T cells showed that iNKT cells inhibit the differentiation of these auto-reactive T cells into effector cells during their priming in pancreatic lymph nodes (PLNs) [13,14].…”

Section: Introductionmentioning

confidence: 65%

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

et al. 2011

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Invariant natural killer T (iNKT) cells are a distinct lineage of innate-like T lymphocytes and converging studies in mouse models have demonstrated the protective role of iNKT cells in the development of type 1 diabetes. Recently, a new subset of iNKT cells, producing high levels of the pro-inflammatory cytokine IL-17, has been identified (iNKT17 cells). Since this cytokine has been implicated in several autoimmune diseases, we have analyzed iNKT17 cell frequency, absolute number and phenotypes in the pancreas and lymphoid organs in non-obese diabetic (NOD) mice. The role of iNKT17 cells in the development of diabetes was investigated using transfer experiments. NOD mice exhibit a higher frequency and absolute number of iNKT17 cells in the lymphoid organs as compared with C57BL/6 mice. iNKT17 cells infiltrate the pancreas of NOD mice where they express IL-17 mRNA. Contrary to the protective role of CD4 1 iNKT cells, the CD4 À iNKT cell population, which contains iNKT17 cells, enhances the incidence of diabetes. Treatment with a blocking anti-IL-17 antibody prevents the exacerbation of the disease. This study reveals that different iNKT cell subsets play distinct roles in the regulation of type 1 diabetes and iNKT17 cells, which are abundant in NOD mice, exacerbate diabetes development.

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“…The expansion of the NKT compartment due to Tg expression of the mouse inv. V␣14-J␣18 rearrangement has also been detected following the injection of the Tg construct directly into nonobese diabetic mice (39,40), indicating that the phenomenon is independent of the mouse's genetic background. Therefore, it is possible that differences in the timing of expression between the Tg human inv.…”

Section: Discussionmentioning

confidence: 96%

Human Invariant Vα24-JαQ TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1− T Cells in Transgenic Mice

Capone

Cantarella

Schumann

et al. 2003

The Journal of Immunology

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A sizable fraction of T cells expressing the NK cell marker NK1.1 (NKT cells) bear a very conserved TCR, characterized by homologous invariant (inv.) TCR Vα24-JαQ and Vα14-Jα18 rearrangements in humans and mice, respectively, and are thus defined as inv. NKT cells. Because human inv. NKT cells recognize mouse CD1d in vitro, we wondered whether a human inv. Vα24 TCR could be selected in vivo by mouse ligands presented by CD1d, thereby supporting the development of inv. NKT cells in mice. Therefore, we generated transgenic (Tg) mice expressing the human inv. Vα24-JαQ TCR chain in all T cells. The expression of the human inv. Vα24 TCR in TCR Cα−/− mice indeed rescues the development of inv. NKT cells, which home preferentially to the liver and respond to the CD1d-restricted ligand α-galactosylceramide (α-GalCer). However, unlike inv. NKT cells from non-Tg mice, the majority of NKT cells in Vα24 Tg mice display a double-negative phenotype, as well as a significant increase in TCR Vβ7 and a corresponding decrease in TCR Vβ8.2 use. Despite the forced expression of the human CD1d-restricted TCR in Cα−/− mice, staining with mCD1d-α-GalCer tetramers reveals that the absolute numbers of peripheral CD1d-dependent T lymphocytes increase at most by 2-fold. This increase is accounted for mainly by an increased fraction of NK1.1− T cells that bind CD1d-α-GalCer tetramers. These findings indicate that human inv. Vα24 TCR supports the development of CD1d-dependent lymphocytes in mice, and argue for a tight homeostatic control on the total number of inv. NKT cells. Thus, human inv. Vα24 TCR-expressing mice are a valuable model to study different aspects of the inv. NKT cell subset.

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NK T Cell-Induced Protection Against Diabetes in Vα14-Jα281 Transgenic Nonobese Diabetic Mice Is Associated with a Th2 Shift Circumscribed Regionally to the Islets and Functionally to Islet Autoantigen

Cited by 109 publications

References 44 publications

Immunoregulation of Autoimmunity by Natural Killer T Cells

Immunoregulation of Autoimmunity by Natural Killer T Cells

NOD mice contain an elevated frequency of iNKT17 cells that exacerbate diabetes

Human Invariant Vα24-JαQ TCR Supports the Development of CD1d-Dependent NK1.1+ and NK1.1− T Cells in Transgenic Mice

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