title: Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice.
abstract: The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag alpha-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease. Recognition of CD1d, either by itself or bound to self-ligands (selfCD1d), could drive NKT cells toward an immunoregulatory phenotype. Hence, ineffective NKT cell-mediated immunoregulation in autoimmune-prone individuals including nonobese diabetic (NOD) mice could be related to defective signals that regulate CD1d expression at time and site of autoimmunity. To test this hypothesis, we transgenically overexpressed CD1d molecules under the control of the insulin promoter within the pancreatic islets of NOD mice (insCD1d). Recognition of overexpressed CD1d molecules rescued NKT cell immunoregulatory function and prevented autoimmune diabetes in insCD1d transgenic NOD mice. Protection from diabetes was associated with a biased IL-4-secreting cytokine phenotype of NKT cells and alteration of the cytokine microenvironment in the pancreatic lymph nodes of transgenic mice. The net effect was a reduced development of the autoimmune T cell repertoire. Our findings suggest that up-regulation of CD1d expression during inflammation is critical to maintain T cell homeostasis and to prevent autoimmunity.
authors.affiliation: Immunology of Diabetes and Islet Transplantation Program, Immunohistochemistry of Rodents Unit, H. San Raffaele Research Institute, Milan, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Falcone
authors.forename: Federica
authors.initials: F
authors.lastname: Facciotti
authors.forename: Nadia
authors.initials: N
authors.lastname: Ghidoli
authors.forename: Paolo
authors.initials: P
authors.lastname: Monti
authors.forename: Stefano
authors.initials: S
authors.lastname: Olivieri
authors.forename: Luca
authors.initials: L
authors.lastname: Zaccagnino
authors.forename: Ezio
authors.initials: E
authors.lastname: Bonifacio
authors.forename: Giulia
authors.initials: G
authors.lastname: Casorati
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanvito
authors.forename: Nora
authors.initials: N
authors.lastname: Sarvetnick
mesh_terms: D000818:Animals; D018949:Antigens, CD1 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D055610:Antigens, CD1d; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D016130:Immunophenotyping; D015847:Interleukin-4 / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000276:immunology*
chemical_list: D018949:Antigens, CD1; D055610:Antigens, CD1d; C526877:CD1D protein, human; D015847:Interleukin-4