Human invariant Vα24+ natural killer T cells activated by α-galactosylceramide (KRN7000) have cytotoxic anti-tumour activity through mechanisms distinct from T cells and natural killer cells

Human V alpha 24 + NKT cells, a subpopulation of natural killer cell receptor (NKR-P1A) expressing T cells with an invariant T-cell receptor (TCR; V alpha 24J alpha Q) are stimulated by the glycolipid, alpha-galactosylceramide (KRN7000), in a CD1d-dependent, TCR-mediated fashion. Little is known about V alpha 24 + NKT-cell function. The murine counterpart, V alpha 14 + NKT cells, appear to have an important role in controlling malignancy. There are no human data examining the role of V alpha 24 + NKT cells in controlling human malignancy. We report that V alpha 24 + NKT cells have perforin-mediated cytotoxicity against haemopoietic malignancies. V alpha 24 TCR, CD1d and alpha-galactosylceramide may all play a role in cytotoxicity but are not absolute requirements. The greatest cytotoxicity was observed against the U937 tumour cell line (95 +/- 5% lysis). THP-1, Molt4, C1R cells and allogeneic mismatched dendritic cells were also sensitive to V alpha 24 + NKT cytotoxicity but neither the NK target, K562, nor lymphokine-activated killer-sensitive Daudi cells, were sensitive. These results indicate a killing pattern distinct from conventional major histocompatibility complex-restricted T cells, NK cells and other cytotoxic lymphoid cells previously described. We conclude that human V alpha 24 + NKT cells have cytotoxic anti-tumour activity against haemopoietic malignancies through effector mechanisms distinct from conventional T cells and NK cells and that their specific stimulator KRN7000 may have therapeutic potential.