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

Abstract

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.

Lack of Chemokine Receptor CCR5 Promotes Murine Fulminant Liver Failure by Preventing the Apoptosis of Activated CD1d-Restricted NKT Cells

“…Indeed, we have shown a direct role for these NKT cells in the development of FLF in Con A-treated CCR5-deficient mice because FLF in these mice was prevented by NKT cell elimination after NK1.1 mAb treatment. Our findings in murine FLF are consistent with observations in murine autoimmune diabetes (43) and experimental allergic asthma (30) where more severe diabetes and airway inflammation in CD1d-deficient NOD mice has been attributed to remnant NKT cells. It is unlikely that an inherent defect in Fas expression or a defective Fas-driven death pathway on CCR5-deficient NKT cells may underlie the resistance of these cells to AICD during Con A-induced fulminant hepatitis.…”

“…In recent years, NKT cells have gained significant attention as targets for immunomodulation primarily due to their ability to secrete high levels of cytokines, including IFN-␥ and IL-4, within minutes of activation (21,22,30). Despite this, the role of NKT cells in the pathology of liver diseases (particularly FLF) remains poorly defined.…”

“…7a). Previous studies have documented increases in IL-4 production by NKT cells following activation with anti-CD3 mAb (25) and ␣-GalCer (22,28,30); therefore, we also examined whether this response is enhanced by CCR5 deficiency. Splenic CCR5-deficient NKT cells were enriched significantly in IL-4 after in vitro activation with anti-CD3 mAb for 5 h (Fig.…”

Transforming Growth Factor-β and Natural Killer T-Cells Are Involved in the Protective Effect of a Bacterial Extract on Type 1 Diabetes

“…We recently reported a critical role for CD1d-dependent NKT cells in exacerbated T-helper type 2-mediated airway inflammation and hyperresponsiveness (34) and in autoimmune diabetes-prone NOD mice (35)(36). The data presented in this article confirm that NKT cells are implicated in type 1 diabetes.…”

Interleukin-13 Pathway Alterations Impair Invariant Natural Killer T-Cell–Mediated Regulation of Effector T Cells in Type 1 Diabetes

“…These differences could be explained by the differentiation state of NOD Teffs and iNKT cells compared with that of humans. However, NOD mice show high basal production of IL-13, so the mechanism proposed for human iNKT cell-mediated regulation could go undetected in this model (52).…”