Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease.
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.
Halder
Ramesh C
RC
Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies, San Diego, California 92121, USA.
Aguilera
Carlos
C
Maricic
Igor
I
Kumar
Vipin
V
D000818:Animals; D018949:Antigens, CD1 / Q000276:immunology; D055610:Antigens, CD1d; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D054426:Chemokine CXCL2; D018925:Chemokines / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D006505:Hepatitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D018664:Interleukin-12 / Q000172:deficiency / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D008024:Ligands; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013433:Sulfoglycosphingolipids / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
D018949:Antigens, CD1; D055610:Antigens, CD1d; D001324:Autoantigens; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D008024:Ligands; D013433:Sulfoglycosphingolipids; D018664:Interleukin-12