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.

Immunoregulation of Autoimmunity by Natural Killer T Cells

“…CD1d deficient mice developed diabetes earlier, had a greater disease penetrance and more severe disease [72,73]. In concordance, upregulation of CD1d expression restored the immunoregulatory function of NKT cells and prevented autoimmune diabetes [74]. Protection conferred by NKT cells was associated with a Th2 shift within the pancreatic islets, and IL-4 has been implicated as a key mediator of immunoregulation [69,75].…”

On/Off TLR Signaling Decides Proinflammatory or Tolerogenic Dendritic Cell Maturation upon CD1d-Mediated Interaction with Invariant NKT Cells

“…Several findings weakened this hypothesis, indicating that secretion of modulatory cytokines, such as IL-10 and IL-4, is dispensable in different models of iNKT cell-induced tolerance (52)(53)(54). Moreover, in most cases, regulatory iNKT cells that suppress T cell immunity and prevent autoimmune diseases do not show a biased regulatory cytokine profile and secrete a diverse array of cytokines, including large amounts of the proinflammatory cytokine IFN-g (6,9,55,56). In this study, we demonstrated that the direct cell-cell contact is crucial for the tolerogenic effect of iNKT cells on DCs whereas iNKT cell-secreted cytokines are dispensable.…”

Involvement of sulfatide in beta cells and type 1 and type 2 diabetes

“…Similarly, overexpression of NKT cells protects Vα14Jα281 transgenic NOD mice against diabetes [48], whereas a shortage of NKT cells in CD1d knock-out mice leads to exacerbation of type 1 diabetes [49]. Finally, upregulation of CD1d expression within the beta cells restores the immunoregulatory function of NKT cells and prevents dia-betes in NOD mice [50]. In the latter study the authors speculate as to the nature of the endogenous ligand that was loaded in the CD1d receptor.…”