Plasticity of Invariant NKT Cell Regulation of Allergic Airway Disease Is Dependent on IFN-γ Production

Abstract

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 recipients, which lack iNKT cells, developed the full spectrum of lung allergic responses following reconstitution with highly purified WT liver or spleen iNKT cells and transfer of OVA-BMDCs, whereas reconstituted recipients of OVA/αGalCer BMDCs failed to do so. Transfer of iNKT cells from IFN-γ−/− mice restored the development of these responses in Jα18-deficient recipients following OVA-BMDC transfer; the responses were enhanced following OVA/αGalCer BMDC transfer. iNKT cells from these IFN-γ−/− mice produced higher levels of IL-13 in vitro compared with WT iNKT cells. These data identify IFN-γ as playing a critical role in dictating the consequences of iNKT cell activation in the initiation phase of the development of AHR and airway inflammation.

CD8+ T activation attenuates CD4+ T proliferation through dendritic cells modification

“…Similarly, our study found that activated CD8 + T induced DCs with tolerogenicity through an IFN-c dependent manner in vitro. Interestingly, previous reports indicated that IFN-c could attenuate CD4 + T mediated airway inflammation by counteracting the Th2 response, remodeling invariant NKT cells, inhibiting eosinophil differentiation, and having direct effects on airway epithelium [46][47][48][49]. But, here we showed that CD8 + T activation in vivo, which resulted in a substantial secretion of IFN-c in BAL, could alleviate airway inflammation in OVA-induced asthma in CD8 + T deficient mice.…”

Dissecting the Roles of Natural Killer T cells in Autoimmune Disorders and Malignancy

“…As a consequence, the development of AHR in a murine model using OVA was blocked [70]. Another study demonstrated that transfer of bone marrow dendritic cells (BMDCs) treated with α-GalCer, prevented the development of lung allergic responses, and this was dependent on IFN-γ production by recipient type I NKT cells [71]. All these findings suggest novel therapeutic strategies for asthma by eliminating or skewing type I NKT cells toward Th1 functions.…”

Role of CD1d- and MR1-Restricted T Cells in Asthma

“…IL-4 or IL-13 production from iNKT cells is required for the development of allergic asthma in mouse models, while iNKT cells can produce IFN-γ, which can suppress the Th2 response and thereby prevent allergic asthma. However, even when employing similar protocols, different institutes obtained completely different findings (33, 36, 37). Since iNKT cells can detect bacterial components through their invariant TCRs or Toll-like receptors, the difference in the lung microbiota may affect the function of distinct iNKT cell subsets, such as NKT1 and NKT2.…”

“…Moreover, a protective role of iNKT cells in allergic asthma was suggested. Subsequent AHR in these models can be suppressed by the systemic activation of iNKT cells by α-GalCer treatment or the transfer of α-GalCer-loaded bone marrow-derived DCs before OVA challenge in an IFN-γ-dependent manner (36, 37). In addition, Grela et al reported that IFN-γ-producing iNKT cells stimulated with toll like receptor (TLR) 7 agonist (R848) attenuated allergic asthma, which is consistent with the finding that TLR7 stimulation not only enhances viral responses but also alleviates experimental asthma (38).…”