Recent advances in the role of NKT cells in allergic diseases and asthma (original) (raw)
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NKT cells contribute to basal IL-4 production but are not required to induce experimental asthma
PloS one, 2017
CD1d-deficiency results in a selective deletion of NKT cells in mice that is reported to prevent murine allergic airway disease (AAD). Because we find 2-3 fold lower basal IL-4 production in CD1d- mice than in wild-type (WT) mice, we hypothesized that the contribution made by NKT cells to AAD would depend on the strength of the stimulus used to induce the disease. Consequently, we compared CD1d-deficient mice to WT mice in the development of AAD, using several models of disease induction that differed in the type and dose of allergen, the site of sensitization and the duration of immunization. Surprisingly we found equivalent allergic inflammation and airway disease in WT and CD1d- mice in all models investigated. Consistent with this, NKT cells constituted only ~2% of CD4+ T cells in the lungs of mice with AAD, and IL-4-transcribing NKT cells did not expand with disease induction. Concerned that the congenital absence of NKT cells might have caused a compensatory shift within the i...
Nature Medicine, 2003
Using natural killer T (NKT) cell-deficient mice, we show here that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, does not develop in the absence of V α 14i NKT cells. The failure of NKT cell-deficient mice to develop AHR is not due to an inability of these mice to produce type 2 T-helper (Th2) responses because NKT cell-deficient mice that are immunized subcutaneously at non-mucosal sites produce normal Th2-biased responses. The failure to develop AHR can be reversed by the adoptive transfer of tetramer-purified NKT cells producing interleukin (IL)-4 and IL-13 to Ja281 −/− mice, which lack the invariant T-cell receptor (TCR) of NKT cells, or by the administration to Cd1d -/mice of recombinant IL-13, which directly affects airway smooth muscle cells. Thus, pulmonary V α 14i NKT cells crucially regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. Therapies that target V α 14i NKT cells may be clinically effective in limiting the development of AHR and asthma.
Proceedings of the National Academy of Sciences, 2006
Asthma is an inflammatory lung disease, in which conventional CD4 ؉ T cells producing IL-4͞IL-13 appear to play an obligatory pathogenic role. Here we show, in a mouse model of asthma, that activation of pulmonary IL-4͞IL-13 producing invariant TCR ؉ CD1drestricted natural killer T (NKT) cells is sufficient for the development of airway hyperreactivity (AHR), a cardinal feature of asthma, in the absence of conventional CD4 ؉ T cells and adaptive immunity. Respiratory administration of glycolipid antigens that specifically activate NKT cells (␣-GalactosylCeramide and a Sphingomonas bacterial glycolipid) rapidly induced AHR and inflammation typically associated with protein allergen administration. Naïve MHC class II-deficient mice, which lack conventional CD4 ؉ T but have NKT cells, showed exaggerated baseline AHR and, when challenged with ␣-GalactosylCeramide, demonstrated even greater AHR. These studies demonstrate an expanded role for NKT cells, in which NKT cells not only produce cytokines that influence adaptive immunity but also function as critical effector cells that can induce AHR. These results suggest that NKT cells responding to glycolipid antigens, as well as conventional CD4 ؉ T cells responding to peptide antigens, may be synergistic in the induction of AHR, although in some cases, each may independently induce AHR. asthma ͉ atopy ͉ IgE
NKT cells regulate the development of asthma
International Congress Series, 2005
Using NKT cell-deficient CD1d knockout and Ja281 knockout mice, we demonstrated that allergen-induced airway hyperreactivity (AHR), a cardinal feature of asthma, failed to develop in the absence of NKT cells. The failure of NKT cell-deficient mice to develop AHR was not due to an inability of these mice to develop Th2 responses and was reversed by adoptive transfer of tetramer purified NKT cells. These studies are the first to show that pulmonary NKT cells critically regulate the development of asthma and Th2-biased respiratory immunity against nominal exogenous antigens. In addition, our studies suggest that therapies that target NKT cells may be clinically effective in limiting the development of AHR and asthma. D 2005 Published by Elsevier B.V.
The Journal of Immunology, 2003
Airway hyperreactivity (AHR), eosinophilic inflammation with a Th2-type cytokine profile, and specific Th2mediated IgE production characterize allergic asthma. In this paper, we show that OVA-immunized J␣18 ؊/؊ mice, which are exclusively deficient in the invariant V␣14 ؉ (iV␣14), 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 iV␣14 NKT cells fully reconstitutes the capacity of J␣18 ؊/؊ mice to develop allergic asthma. Also, specific tetramer staining shows that OVA-immunized WT mice have activated (CD69 ؉) iV␣14 NKT cells. Importantly, anti-CD1d mAb treatment blocked the ability of iV␣14 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 iV␣14 NKT cells are required to participate in allergen-induced Th2 airway inflammation through a CD1d-dependent mechanism.
The Journal of Immunology, 2003
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 particip...
Invariant NKT cells are required for airway inflammation induced by environmental antigens
Journal of Experimental Medicine, 2011
. These data demonstrate that iNKT cell antigens are far more widely dispersed in the environment than previously anticipated. Furthermore, as the antigenic activity in different houses varied greatly, they further suggest that iNKT cell responses to ambient antigens, particular to certain environments, might promote sensitization to conventional respiratory allergens.
CD4+ Invariant T-Cell–Receptor+ Natural Killer T Cells in Bronchial Asthma
New England Journal of Medicine, 2006
Background Bronchial asthma is associated with an inflammatory process that is characterized by the presence in the airways of large numbers of CD4+ T cells producing interleukin-4 and interleukin-13. However, the CD4 antigen is expressed not only by class II major histocompatibility complex (MHC)-restricted CD4+ T cells, but also by a newly identified subgroup of T cells, CD1d-restricted natural killer T cells. These cells express a conserved (invariant) T-cell receptor and have a potent immunoregulatory function. Because mouse models of allergic asthma indicate that natural killer T cells are required for the development of allergen-induced airway hyperreactivity, we hypothesized that natural killer T cells play an important role in human asthma. Methods We used CD1d-tetramers, antibodies specific for natural killer T cells, as well as reverse-transcriptase-polymerase-chain-reaction analysis of the invariant T-cell receptor of natural killer T cells to assess the frequency and distribution of natural killer T cells in the lungs and in the circulating blood of 14 patients with asthma. Results About 60 percent of the pulmonary CD4+CD3+ cells in patients with moderate-tosevere persistent asthma were not class II MHC-restricted CD4+ T cells but, rather, natural killer T cells. The natural killer T cells expressed an invariant T-cell receptor and produced type 2 helper cytokines. In contrast, the CD4+ T cells found in the lungs of patients with sarcoidosis were conventional CD4+CD3+ T cells, not natural killer T cells. Conclusions Together with studies in mice indicating a requirement for natural killer T cells in the development of allergen-induced airway hyperreactivity, our results strongly suggest that CD4+ natural killer T cells play a prominent pathogenic role in human asthma.