The aim of this study was to investigate the roles and mechanism of interleukin-12 (IL-12) and interleukin-18 (IL-18) in potentiating the autoreactivity of lymphoid cells specific for P2 53-78 peptide. P2 53-78-specific lymphoid cells in the presence of IL-12 or IL-18 alone passive transferred only moderate experimental autoimmune neuritis (EAN) into a low percentage of recipients. However, lymphoid cells co-cultured with both cytokines transferred aggressive clinical and histological EAN into all recipients. NKR-P1+ cells (including NK and NKT cells) played an immunosuppressive function in passive transfer EAN and depletion of NKR-P1+ cells by anti-NKR-P1 Ab and complement induced a more serious form of EAN. Nevertheless, lymphoid cells co-cultured with both IL-12 and IL-18 induced high levels of interferon-gamma (IFN-gamma) and promoted Th1 differentiation partially through NKR-P1+ cells and to some extent, NKR-P1+ cell depletion inhibited the auto-reactivity of lymphoid cells treated with IL-12 and IL-18.