The natural killer–activating receptor, NKG2D, on CD3+CD8+ T cells plays a critical role in identifying and killing autologous myeloma cells

Background The NKG 2 D receptor, one of the natural killer ( NK ) cell–activating receptors, is expressed on the surface of CD 3+ CD 8+ T cells, γδ+ T cells, NK cells, NKT cells, and a few CD 4+ T cells. We show, for the first time, a critical role for the NKG 2 D receptor on CD 3+ CD 8+ T cells isolated from myeloma patients, in identifying and killing autologous myeloma cells isolated from the same patients’ marrow. We also show that blocking NKG 2 D using anti‐ NKG 2 D reverses the cytotoxicity while blocking HLA ‐ I using antibodies does not have the same effect, showing that the autologous cytotoxicity is NKG 2 D dependent and major histocompatibility complex ( MHC )‐ I independent. We further confirmed the NKG 2 D specificity by small interfering RNA ( siRNA ) down regulation of NKG 2 D receptor. Study Design and Methods Using ex vivo expansion methods that enrich for NKG 2 D + CD 3+ CD 8+ T cells, we investigated whether these ex vivo expanded NKG 2 D + CD 3+ CD 8+ T cells would recognize and lyse autologous and allogeneic myeloma cells, independent of T ‐cell receptor or MHC ‐ I expression. Results Myeloma cell lysis by the NKG 2 D + CD 3+ CD 8+ T cells correlated with the amount of NKG 2 D ligand expression. With receptor–ligand interaction, interferon‐γ and tumor necrosis factor‐α were released. Blocking the NKG 2 D receptor by using either monoclonal antibodies or si RNAs inhibited the receptor's function and prevented myeloma cell lysis. Conclusion Clinical trials are ongoing to determine a correlation with the number and function of NKG 2 D + CD 3+ CD 8+ T cells and clinical outcomes in transplanted myeloma patients, including lymphocyte recovery following transplant and overall survival.