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- Title
The natural killer-activating receptor, NKG2 D, on CD3+ CD8+ T cells plays a critical role in identifying and killing autologous myeloma cells.
- Authors
Talebian, Laleh; Fischer, Dawn A.; Wu, Jillian; Channon, Jacqueline Y.; Sentman, Charles L.; Ernstoff, Marc S.; Meehan, Kenneth R.
- Abstract
Background The NKG2 D receptor, one of the natural killer ( NK) cell-activating receptors, is expressed on the surface of CD3+ CD8+ T cells, γδ+ T cells, NK cells, NKT cells, and a few CD4+ T cells. We show, for the first time, a critical role for the NKG2 D receptor on CD3+ CD8+ T cells isolated from myeloma patients, in identifying and killing autologous myeloma cells isolated from the same patients' marrow. We also show that blocking NKG2 D using anti- NKG2 D reverses the cytotoxicity while blocking HLA- I using antibodies does not have the same effect, showing that the autologous cytotoxicity is NKG2 D dependent and major histocompatibility complex ( MHC)- I independent. We further confirmed the NKG2 D specificity by small interfering RNA ( siRNA) down regulation of NKG2 D receptor. Study Design and Methods Using ex vivo expansion methods that enrich for NKG2 D+ CD3+ CD8+ T cells, we investigated whether these ex vivo expanded NKG2 D+ CD3+ CD8+ 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 NKG2 D+ CD3+ CD8+ T cells correlated with the amount of NKG2 D ligand expression. With receptor-ligand interaction, interferon-γ and tumor necrosis factor-α were released. Blocking the NKG2 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 NKG2 D+ CD3+ CD8+ T cells and clinical outcomes in transplanted myeloma patients, including lymphocyte recovery following transplant and overall survival.
- Subjects
KILLER cells; MULTIPLE myeloma; CELL receptors; CD3 antigen; MYELOMA proteins; CD4 antigen; SMALL interfering RNA; PATIENTS
- Publication
Transfusion, 2014, Vol 54, Issue 6, p1515
- ISSN
0041-1132
- Publication type
Article
- DOI
10.1111/trf.12517