i(3)so3-galactosylceramide and Asthma

Our previous study showed that sulfatide-activated type II natural killer T (NKT) cells can prevent allergic airway inflammation in an ovalbumin (OVA)-induced murine model of asthma, but the underlying mechanism is unclear. Recently, sulfatide-activated type II NKT cells were shown to modulate the function of dendritic cells in experimental autoimmune encephalomyelitis and nonobese diabetic mice. Thus, it was hypothesized that sulfatide-activated type II NKT cells may modulate the function of lung dendritic cells (LDCs) in asthmatic mice. Our data showed that, in our mouse models, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells resulted in reduced expression of surface maturation markers and proinflammatory cytokine production of LDCs. LDCs from sulfatide-treated asthmatic mice, in contrast to LDCs from PBS-treated asthmatic mice, significantly reduced allergic airway inflammation in vivo. However, we found no influence of sulfatide-activated type II NKT cells on the phenotypic and functional maturation of bone marrow-derived dendritic cells in vitro. In addition, adoptive transfer of sulfatide-activated type II NKT cells did not influence the phenotypic and functional maturation of LDCs in CD1d

Topics: Animals; Asthma; Dendritic Cells; Female; Inflammation Mediators; Lung; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Natural Killer T-Cells; Ovalbumin; Sulfoglycosphingolipids

Asthma is a common chronic inflammatory disease involving many different cell types. Recently, type I natural killer T (NKT) cells have been demonstrated to play a crucial role in the development of asthma. However, the roles of type II NKT cells in asthma have not been investigated before. Interestingly, type I and type II NKT cells have been shown to have opposing roles in antitumor immunity, antiparasite immunity, and autoimmunity. We hypothesized that sulfatide-activated type II NKT cells could prevent allergic airway inflammation by inhibiting type I NKT cell function in asthma. Strikingly, in our mouse model, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells result in reduced-inflammation cell infiltration in the lung and bronchoalveolar lavage fluid, decreased levels of IL-4 and IL-5 in the BALF; and decreased serum levels of ovalbumin-specific IgE and IgG1. Furthermore, it is found that the activation of sulfatide-reactive type II NKT cells leads to the functional inactivation of type I NKT cells, including the proliferation and cytokine secretion. Our data reveal that type II NKT cells activated by glycolipids, such as sulfatide, may serve as a novel approach to treat allergic diseases and other disorders characterized by inappropriate type I NKT cell activation.

Topics: Adoptive Transfer; Animals; Asthma; Bronchoalveolar Lavage Fluid; Female; Goblet Cells; Hyperplasia; Immunoglobulin E; Immunoglobulin G; Interleukin-4; Interleukin-5; Lung; Mice; Mice, Inbred BALB C; Natural Killer T-Cells; Ovalbumin; Respiratory Mucosa; Sulfoglycosphingolipids

Because of the paucity of known self lipid-reactive ligands for NKT cells, interactions among distinct NKT cell subsets as well as immune consequences following recognition of self glycolipids have not previously been investigated. Here we examined cellular interactions and subsequent immune regulatory mechanism following recognition of sulfatide, a self-glycolipid ligand for a subset of CD1d-restricted type II NKT cells. Using glycolipid/CD1d tetramers and cytokine responses, we showed that activation of sulfatide-reactive type II NKT cells and plasmacytoid DCs caused IL-12- and MIP-2-dependent recruitment of type I, or invariant, NKT (iNKT) cells into mouse livers. These recruited iNKT cells were anergic and prevented concanavalin A-induced (ConA-induced) hepatitis by specifically blocking effector pathways, including the cytokine burst and neutrophil recruitment that follow ConA injection. Hepatic DCs from IL-12(+/+) mice, but not IL-12(-/-) mice, adoptively transferred anergy in recipients; thus, IL-12 secretion by DCs enables them to induce anergy in iNKT cells. Our data reveal what we believe to be a novel mechanism in which interactions among type II NKT cells and hepatic DCs result in regulation of iNKT cell activity that can be exploited for intervention in inflammatory diseases, including autoimmunity and asthma.

Topics: Animals; Antigens, CD1; Antigens, CD1d; Asthma; Autoantigens; Autoimmunity; Chemokine CXCL2; Chemokines; Clonal Anergy; Dendritic Cells; Hepatitis; Interleukin-12; Killer Cells, Natural; Ligands; Liver; Mice; Mice, Knockout; Sulfoglycosphingolipids; T-Lymphocytes