Cutting Edge: Invariant Vα14 NKT Cells Are Required for Allergen-Induced Airway Inflammation and Hyperreactivity in an Experimental Asthma Model (original) (raw)
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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.
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.
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...
Recent advances in the role of NKT cells in allergic diseases and asthma
Current Allergy and Asthma Reports, 2008
Asthma is the result of chronic airway inflammation that is dominated by the presence of eosinophils and CD4 + T lymphocytes. CD4 + T cells include several subsets and play a critical role in orchestrating the inflammation, predominantly by secreting interleukin-4 and interleukin-13. Recently, research identified a new subset of T cells, natural killer T (NKT) cells, which also express the CD4 marker. In contrast to conventional CD4 + T cells, NKT cells do not respond to peptide antigens, but rather to glycolipids. In animal models of asthma, direct activation of NKT cells by glycolipids results in the secretion of extensive amounts of cytokines and triggers the development of airway hyperreactivity. Moreover, in patients with chronic asthma, NKT cells can be found in bronchoalveolar lavage fluids in significant amounts. These data strongly suggest that NKT cells play an important role in asthma pathogenesis.
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.
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.
The Journal of Immunology, 2010
Invariant NKT cells (iNKT cells) play a pivotal role in the development of allergen-induced airway hyperresponsiveness (AHR) and inflammation. However, it is unclear what role they play in the initiation (sensitization) phase as opposed to the effector (challenge) phase. The role of iNKT cells during sensitization was examined by determining the response of mice to intratracheal transfer of OVA-pulsed or OVA–α-galactosylceramide (OVA/αGalCer)-pulsed bone marrow-derived dendritic cells (BMDCs) prior to allergen challenge. Wild-type (WT) recipients of OVA-BMDCs developed AHR, increased airway eosinophilia, and increased levels of Th2 cytokines in bronchoalveolar lavage fluid, whereas recipients of OVA/αGalCer BMDCs failed to do so. In contrast, transfer of these same OVA/αGalCer BMDCs into IFN-γ–deficient (IFN-γ−/−) mice enhanced the development of these lung allergic responses, which was reversed by exogenous IFN-γ treatment following OVA-BMDC transfer. Further, Jα18-deficient recipi...