Ectopic expression of retinoic acid early inducible-1 gene (RAE-1) permitsnatural killer cell-mediated rejection of a MHC class I-bearing tumor in vivo

In 1986, Karre and colleagues reported that natural killer (NK) cells rejec ted an MHC class I-deficient tumor cell line (RMA-S) but they did not rejec t the same cell line if it expressed MHC class I (RMA). Based on this obser vation, they proposed the concept that NK cells provide immune surveillance for "missing self," e.g., they eliminate cells that have lost class I MHC antigens. This seminal observation predicted the existence of inhibitory NK cell receptors for MHC class I. Here, we present evidence that NK cells ar e able to reject tumors expressing MHC class I if the tumor expresses a lig and for NKG2D. Mock-transfected RMA cells resulted in tumor formation. In c ontrast, when RMA cells were transfected with the retinoic acid early induc ible gene-1 gamma or delta (RAE-1), ligands for the activating receptor NKG 2D, the tumors were rejected. The tumor rejection was mediated by NK cells, and not by CD1-restricted NK1.1(+) T cells. No T cell-mediated immunologic al memory against the parental tumor was generated in the animals that had rejected the RAE-1 transfected tumors, which succumbed to rechallenge with the parental RMA tumor. Therefore, NK cells are able to reject a tumor expr essing RAE-1 molecules, despite expression of self MHC class I on the tumor , demonstrating the potential for NK cells to participate in immunity again st class I-bearing malignancies.