Cutting Edge: Vα14-Jα281 NKT Cells Naturally Regulate Experimental Autoimmune Encephalomyelitis in Nonobese Diabetic Mice

Mars, Lennart T.; Laloux, Véronique; Goude, Karine; Desbois, Sabine; Saoudi, Abdelhadi; Kaer, Luc Van; Lassmann, Hans; Herbelin, André; Lehuen, Agnès; Liblau, Roland

doi:10.4049/jimmunol.168.12.6007

Cited by 133 publications

(114 citation statements)

References 28 publications

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“…The data actually support the opposite, that NKT cells might act as suppressor cells, and a deficiency in this cell subset might contribute to pathogenesis. This is consistent with an accumulating body of evidence that NKT cells inhibit the development of autoimmunity (21)(22)(23) and with recent observations that NKT cells are deficient in several human autoimmune diseases, among them AIH (24).…”

Section: Discussionsupporting

confidence: 73%

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Rudner¹,

Lin

Park

et al. 2003

The Journal of Immunology

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The etiology of autoimmune liver disease is poorly understood. BALB/c mice deficient in the immunoregulatory cytokine TGF-β1 spontaneously develop necroinflammatory liver disease, but the immune basis for the development of this pathology has not been demonstrated. Here, we show that BALB/c-TGF-β1−/− mice exhibit abnormal expansion in hepatic mononuclear cells (MNCs) compared with wild-type littermate control mice, particularly in the T cell and macrophage lineages. To test whether lymphocytes of the adaptive immune system are required for the spontaneous development of necroinflammatory liver disease, BALB/c-TGF-β1−/− mice were rendered deficient in B and T cells by crossing them with BALB/c-recombinase-activating gene 1−/− mice. BALB/c-TGF-β1−/−/recombinase-activating gene 1−/− double-knockout mice showed extended survival and did not develop necroinflammatory liver disease. The cytolytic activity of BALB/c-TGF-β1−/− hepatic lymphocytes was assessed using an in vitro CTL assay. CTL activity was much higher in BALB/c-TGF-β1−/− hepatic MNCs compared with littermate control hepatic MNCs and was particularly pronounced in the CD4+ T cell subset. Experimental depletion of CD4+ T cells in young BALB/c-TGF-β1−/− mice prevented the subsequent development of necroinflammatory liver disease, indicating that CD4+ T cells are essential for disease pathogenesis in vivo. These data definitively establish an immune-mediated etiology for necroinflammatory liver disease in BALB/c-TGF-β1−/− mice and demonstrate the importance of CD4+ T cells in disease pathogenesis in vivo. Furthermore, TGF-β1 has a critical role in homeostatic regulation of the hepatic immune system, inhibiting the development or expansion of hepatic cytolytic CD4+ T cells.

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Section: Discussionsupporting

confidence: 73%

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Rudner¹,

Lin

Park

et al. 2003

The Journal of Immunology

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“…Yet, it remains to be examined whether in a model of immune dysregulation like that of NOD mice, allergen-specific Tr cells are defective. NKT cells, another subset of Tr lymphocytes regulate immune responses in several models of autoimmunity in the NOD strain, including EAE and type 1 diabetes [28,38,39]. They have recently been shown to be required in allergen-induced Th2 airway inflammation in mice, which are not susceptible to autoimmune diseases [24,25].…”

Section: Discussionmentioning

confidence: 99%

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

et al. 2004

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The NOD mouse has proved to be a relevant model of insulin-dependent diabetes mellitus, closely resembling the human disease. However, it is unknown whether this strain presents a general bias toward Th1-mediated autoimmunity or remains capable of mounting complete Th2-mediated responses. Here, we show that NOD mice have the capacity to develop a typical Th2-mediated disease, namely experimental allergic asthma. In contrast to what might have been expected, they even developed a stronger Th2-mediated pulmonary inflammatory response than BALB/c mice, a strain that shows a typical Th2 bias in this model. Thus, after allergen sensitization and intra-nasal challenge, the typical features of experimental asthma were exacerbated in NOD mice, including enhanced bronchopulmonary responsiveness, mucus production and eosinophilic inflammation in the lungs as well as specific IgE titers in serum. These hallmarks of allergic asthma were associated with increased IL-4, IL-5, IL-13 and eotaxin production in the lungs, as compared with BALB/c mice. Notwithstanding their quantitative and functional defect in NOD mice, CD1d-dependent NKT cells contribute to aggravate the disease, since in OVA-immunized CD1d -/-NOD mice, which are deficient in this particular T cell subset, airway eosinophilia was clearly diminished relative to NOD littermates. This is the first evidence that autoimmune diabetesprone NOD mice can also give rise to enhanced Th2-mediated responses and might thus provide a useful model for the study of common genetic and cellular components, including NKT cells that contribute to both asthma and type 1 diabetes.

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“…injections of pertussis toxin (day 0, 200 ng; day 2, 400 ng; List Biological Laboratories). Disease severity was monitored daily (28). Where indicated, mice were treated with two 4-g doses of ␣-GalCer (Kirin Brewery) on day 0 (emulsified in the MOG CFA mixture) and day 4 (i.p.)…”

Section: Methodsmentioning

confidence: 99%

Invariant NKT cells inhibit development of the Th ₁₇ lineage

Mars

Araujo²,

Kerschen³

et al. 2009

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

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Cutting Edge: Vα14-Jα281 NKT Cells Naturally Regulate Experimental Autoimmune Encephalomyelitis in Nonobese Diabetic Mice

Cited by 133 publications

References 28 publications

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

Invariant NKT cells inhibit development of the Th ₁₇ lineage

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Cutting Edge: Vα14-Jα281 NKT Cells Naturally Regulate Experimental Autoimmune Encephalomyelitis in Nonobese Diabetic Mice

Cited by 133 publications

References 28 publications

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Necroinflammatory Liver Disease in BALB/c Background, TGF-β1-Deficient Mice Requires CD4+ T Cells

Exacerbated Th2‐mediated airway inflammation and hyperresponsiveness in autoimmune diabetes‐prone NOD mice: a critical role for CD1d‐dependent NKT cells

Invariant NKT cells inhibit development of the Th 17 lineage

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Invariant NKT cells inhibit development of the Th ₁₇ lineage