Costimulation-dependent modulation of experimental autoimmune encephalomyelitis by ligand stimulation of V alpha 14 NK T cells

Experimental autoimmune encephalomyelitis (EAE) is a Th1 cell-mediated autoimmune disease that can be protected against by stimulating regulatory cells. Here we examined whether EAE can be purposefully modulated by stimulating V alpha 14 NK T cells with the CD1d-restricted ligand alpha -galactosylceramide (alpha -GC), EAE induced in wild-type C57BL/6 (B6) mice was not appreciably altered by injection of alpha -GC. However, EAE induced in IL-4 knockout mice and IFN-gamma knockout mire was enhanced or suppressed by alpha -GC, respectively. This indicates that the IL-4 and IFN-gamma triggered by alpha -GC may play an inhibitory or enhancing role in the regulation of EAE, We next studied whether NK T cells of wild-type mice may switch their Th0-like phenotype toward Th1 or Th2, Notably, in the presence of blocking B7.2 (CD86) mAb, alpha -GC stimulation could bias the cytokine profile of NK T cells toward Th2, whereas presentation of alpha -GC by CD40-activated APC induced a Th1 shift of NK T cells. Furthermore, transfer of the alpha -GC-pulsed APC preparations suppressed or enhanced EAE according to their ability to polarize NK T cells toward Th2 or Th1 in vitro. These results have important implications for understanding the role of NK T cells in autoimmunity and for designing a therapeutic strategy targeting NK T cells.