Airway hyperreactivity (AHR), eosinophilic inflammation with a Th2-type cytokine profile, and specific Th2-mediated IgE production characterize allergic asthma. In this paper, we show that OVA-immunized Jα18−/− mice, which are exclusively deficient in the invariant Vα14+ (iVα14), CD1d-restricted NKT cells, exhibit impaired AHR and airway eosinophilia, decreased IL-4 and IL-5 production in bronchoalveolar lavage fluid, and reduced OVA-specific IgE compared with wild-type (WT) littermates. Adoptive transfer of WT iVα14 NKT cells fully reconstitutes the capacity of Jα18−/− mice to develop allergic asthma. Also, specific tetramer staining shows that OVA-immunized WT mice have activated (CD69+) iVα14 NKT cells. Importantly, anti-CD1d mAb treatment blocked the ability of iVα14 T cells to amplify eosinophil recruitment to airways, and both Th2 cytokine and IgE production following OVA challenge. In conclusion, these findings clearly demonstrate that iVα14 NKT cells are required to participate in allergen-induced Th2 airway inflammation through a CD1d-dependent mechanism.

IL-33 has recently been identified as a cytokine endowed with pro-Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL-4 producers. Here, we report a two-fold increase of iNKT-cell counts in spleen and liver after a 7-day treatment of mice with IL-33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL-33 by in vitro expansion and functional activation. Conversely to the expected pro-Th2 effect, IL-33 induced a preferential increase in IFN-c rather than IL-4 production upon TCR engagement that depended on endogenous IL-12. Moreover, in combination with the pro-inflammatory cytokine IL-12, IL-33 enhanced IFN-c production by both iNKT and NK cells. Taken together these data support the conclusion that IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses.Key words: Cytokines . Inflammation . Natural killer cells . Natural killer T cells .Th1/Th2 cells Introduction IL-33 (or IL-1F11) has recently been identified as a ligand of the orphan T1/ST2 receptor, a member of the IL-1 receptor (IL-1R) family [1] that was initially described as a nuclear factor, nuclear factor from high endothelial venules, abundantly expressed by endothelial cells in lymphoid tissues [2,3]. IL-33 induces its biological effects through a heterodimeric complex comprising the T1/ST2 receptor [1] and the IL-1R accessory protein (IL-1RAcP), another member of IL-1R family [4,5]. T1/ST2 engagement triggers a signalling pathway that requires MyD88 and NF-kB [1,4,6]. It has long been known that T1/ST2 is expressed primarily in mast and Th2 cells and is associated with important Th2 effector functions [7][8][9]. Accordingly, IL-33 has been found to promote Th2 cytokine production by mast cells and polarized T cells in vitro, and to induce pulmonary and mucosal Th2 inflammation when administered in vivo [1].iNKT cells constitute a distinctive subpopulation of mature ab-T cells bearing an invariant TCR a-chain together with NK-cell receptors [10,11]. They recognize glycosphingolipid Ags presented by CD1d, a non-classical class I-like Ag-presenting molecule, and respond rapidly to TCR stimulation with a-galactosylceramide (a-GC) by generating a number of cytokines, 1046particularly 11]. In most disease models in which iNKT cells have been implicated their beneficial or detrimental effects have been ascribed to either Th1 or Th2 cytokines [10,11]. It has also been established that the balance between these two profiles depends essentially on the microenvironment, which favours IL-4 or IFN-g production [12][13][14][15][16][17].Given its previously established pro-Th2 functions, IL-33 seemed a plausible candidate for the regulation of iNKT-cell activities, prompting us to investigate whether it could directly interact with this regulatory cell subset to drive IL-4 production. Starting from the observation that the incidence of iNKT cells was increased in spleen and liver of mice injected with ...

Allergic asthma is a multifaceted syndrome consisting of eosinophil‐rich airway inflammation, bronchospasm, and airway hyper‐responsiveness (AHR). Using a mouse model of allergic asthma, we previously reported that invariant NKT (iNKT) cells increase the severity of this disease. Herein, we demonstrate that a single i.v. injection of α‐galactosylceramide (α‐GalCer), 1 h before the first airway allergen challenge of OVA‐sensitized mice, abrogates elicitation of AHR, airway eosinophilia, IL‐4 and IL‐5 production in bronchoalveolar lavage fluid, and specific anti‐OVA IgE antibodies. Further, α‐GalCer administered intranasally also strongly inhibited the major symptoms of asthma in sensitized and challenged mice. α‐GalCer treatment induces iNKT cell accumulation in the lungs, and shifts their cytokine profile from pro‐asthmatic IL‐4 to a protective IFN‐γ production. The role of IFN‐γ from iNKT cells in protection was shown by adoptive transfer of sorted iNKT cells from OVA‐sensitized and α‐GalCer‐treated mice which protected immunized recipients from manifesting asthma by an IFN‐γ‐dependent pathway. Our findings demonstrate for the first time that α‐GalCer administered locally inhibits asthma symptoms, even in predisposed asthmatic mice, through an iNKT cell‐ and IFN‐γ‐dependent pathway. See accompanying commentary:

Mechanisms accounting for gender dimorphism during immune responses are still poorly understood. Since invariant natural killer T (iNKT) cells exert important regulatory functions through their capacity to produce both T helper 1 (Th1) and Th2 cytokines, we addressed the question of whether these activities could be modulated by sexual hormones. We found that in vivo challenge with the specific ligand of iNKT cells, alpha-galactosylceramide (alpha-GalCer), induced significantly higher concentrations of interferon gamma (IFN-gamma) in the serum of female than in that of male mice, while interleukin 4 (IL-4) production was not modified. In support of a crucial role of ovarian hormones in this phenomenon, a significant decrease of serum IFN-gamma concentrations occurred in ovariectomized females, in response to treatment with alpha-GalCer, while orchidectomy affected neither IFN-gamma nor IL-4 serum concentrations in males. The implication of estrogens in this selective enhancement of IFN-gamma production by iNKT cells was demonstrated by (1) the increased alpha-GalCer-induced IFN-gamma synthesis by iNKT cells upon both in vitro and in vivo exposure to estradiol and (2) the abolition of the sex-linked difference in alpha-GalCer-induced IFN-gamma release in estrogen receptor alpha-deficient mice. These results provide the first evidence that estrogens influence iNKT cells leading to this gender dimorphism in their cytokine production profile.

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Invariant natural killer T (iNKT) cells are a unique lymphocyte subtype implicated in the regulation of autoimmunity and a good source of protective Th2 cytokines. Agonist α‐galactosylceramide (α‐GalCer) of iNKT cells exert a therapeutical effect in type 1 diabetes. We investigated whether iNKT activation with α‐GalCer was protective in collagen‐induced arthritis (CIA) in DBA/1 mice, a standard model of rheumatoid arthritis. Here, we have shown that in vivo iNKT cell function was altered in DBA/1 mice since stimulation with α‐GalCer led to decreased IL‐4 and IFN‐γ levels in sera, as compared with C57BL/6 mice. α‐GalCer induced a clear‐cut diminution of clinical and histological arthritides. An anti‐IL‐10 receptor antibody abrogated the protective effect of α‐GalCer, suggesting a key role for IL‐10 in the protection against CIA by activated iNKT cells. Confirming these data, disease protection conferred by α‐GalCer correlated with the ability of LN CD4+ cells to secrete larger amounts of IL‐10. These findings suggest that in CIA susceptibility to autoimmunity is associated with dysfunctions of iNKT cells. Our demonstration that iNKT cell activation by α‐GalCer remains efficient in CIA‐prone DBA/1 mice to provide protective IL‐10 suggests that this could be used therapeutically to treat autoimmune arthritis.

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.