Modulation of Vα19 NKT cell immune responses by α‐mannosyl ceramide derivatives consisting of a series of modified sphingosines

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Abstract
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 Th1‐ 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.