Impaired SLAM-SLAM homotypic interaction between invariant NKT cells and dendritic cells affects differentiation of IL-4/IL-10-secreting NKT2 cells in nonobese diabetic mice.
The regulatory function of invariant NKT (iNKT) cells for tolerance induction and prevention of autoimmunity is linked to a specific cytokine profile that comprises the secretion of type 2 cytokines like IL-4 and IL-10 (NKT2 cytokine profile). The mechanism responsible for iNKT cell differentiation toward a type 2 phenotype is unknown. Herein we show that costimulatory signals provided by the surface receptor signaling lymphocytic activation molecule (SLAM) on myeloid dendritic cells (mDC) to iNKT cells is crucial for NKT2 orientation. Additionally, we demonstrate that the impaired acquisition of an NKT2 cytokine phenotype in nonobese diabetic (NOD) mice that spontaneously develop autoimmune diabetes is due to defective SLAM-induced signals generated by NOD mDC. Mature mDC of C57BL/6 mice express SLAM and induce C57BL/6 or NOD iNKT cells to acquire a predominant NKT2 cytokine phenotype in response to antigenic stimulation with the iNKT cell-specific Ag, the alpha-galactosylceramide. In contrast, mature NOD mDC express significantly lower levels of SLAM and are unable to promote GATA-3 (the SLAM-induced intracellular signal) up-regulation and IL-4/IL-10 production in iNKT cells from NOD or C57BL/6 mice. NOD mice carry a genetic defect of the Slamf1 gene that is associated with reduced SLAM expression on double-positive thymocytes and altered iNKT cell development in the thymus. Our data suggest that the genetic Slamf1 defect in NOD mice also affects SLAM expression on other immune cells such as the mDC, thus critically impairing the peripheral differentiation of iNKT cells toward a regulatory NKT2 type.
Baev
Denis V
DV
Experimental Diabetes Unit, San Raffaele Scientific Institute, Milan, Italy.
Caielli
Simone
S
Ronchi
Francesca
F
Coccia
Margherita
M
Facciotti
Federica
F
Nichols
Kim E
KE
Falcone
Marika
M
D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D015703:Antigens, CD; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D011956:Receptors, Cell Surface; C000604062:Slamf1 protein, mouse; D016753:Interleukin-10; D000071177:Signaling Lymphocytic Activation Molecule Family Member 1; D015847:Interleukin-4