We have demonstrated that analogues of α-mannosyl ceramide (α-ManCer) consisting of a series of immunosuppressive 2-aminoalcohol derivatives in place of sphingosine promote a greater immune response from mouse invariant Vα19-Jα26 (AV19-AJ33) TCR-bearing NKT (Vα19 NKT) cells than α-ManCer itself. To further characterize the immune responses of Vα19 NKT cells to the α-ManCer analogues, cytokine production by the cells was examined in detail. We found that certain α-ManCer derivatives individually induced either Th1- or Th2-dominant cytokine production in culture. The Th1- or Th2-biased immune responses of Vα19 NKT cells were dependent on MHC class I-like MR1, since they were induced by coculture with the MR1 transfectants previously loaded with the glycolipids and were inhibited in the presence of anti-MR1 antiserum. Presumably, the recognition of the α-mannosyl residue of the α-ManCer analogues by the invariant TCR is individually modulated, depending on the altered interaction with the groove of the antigen-presenting MR1. Priming of the Vα19 invariant TCR-transgenic mice in vivo with these glycolipid derivatives resulted in the induction of the Thl- or Th2-biased immune responses. Thus, these α-ManCer derivatives are likely to be useful in immunotherapy for either Th1 or Th2 excess autoimmune diseases, modulating the function of Vα19 NKT cells.
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