This study was sponsored in part by a grant from the Hitchcock Foundation, Geisel School of Medicine and the Dartmouth-Hitchcock Medical Center (KRM), Leukemia and Lymphoma Society Translational Research Grant 6061-06 (KRM), Dartmouth College COBRE Grant 5P20RR016437-07 (KRM, MSE), CA112761 (KRM, MSE), CA095648 (MSE), and CA130911 (CLS).
TRANSPLANTATION AND CELLULAR ENGINEERING
The natural killer–activating receptor, NKG2D, on CD3+CD8+ T cells plays a critical role in identifying and killing autologous myeloma cells
Article first published online: 22 JAN 2014
© 2014 AABB
Volume 54, Issue 6, pages 1515–1521, June 2014
How to Cite
Talebian, L., Fischer, D. A., Wu, J., Channon, J. Y., Sentman, C. L., Ernstoff, M. S. and Meehan, K. R. (2014), The natural killer–activating receptor, NKG2D, on CD3+CD8+ T cells plays a critical role in identifying and killing autologous myeloma cells. Transfusion, 54: 1515–1521. doi: 10.1111/trf.12517
- Issue published online: 9 JUN 2014
- Article first published online: 22 JAN 2014
- Manuscript Accepted: 25 OCT 2013
- Manuscript Revised: 23 OCT 2013
- Manuscript Received: 3 JUL 2013
- Hitchcock Foundation
- Geisel School of Medicine and the Dartmouth-Hitchcock Medical Center
- Leukemia and Lymphoma Society Translational Research Grant. Grant Number: 6061-06
- Dartmouth College COBRE Grant. Grant Numbers: 5P20RR016437-07, CA112761, CA095648, CA130911
The NKG2D 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 NKG2D 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 NKG2D using anti-NKG2D reverses the cytotoxicity while blocking HLA-I using antibodies does not have the same effect, showing that the autologous cytotoxicity is NKG2D dependent and major histocompatibility complex (MHC)-I independent. We further confirmed the NKG2D specificity by small interfering RNA (siRNA) down regulation of NKG2D receptor.
Study Design and Methods
Using ex vivo expansion methods that enrich for NKG2D+CD3+CD8+ T cells, we investigated whether these ex vivo expanded NKG2D+CD3+CD8+ T cells would recognize and lyse autologous and allogeneic myeloma cells, independent of T-cell receptor or MHC-I expression.
Myeloma cell lysis by the NKG2D+CD3+CD8+ T cells correlated with the amount of NKG2D ligand expression. With receptor–ligand interaction, interferon-γ and tumor necrosis factor-α were released. Blocking the NKG2D receptor by using either monoclonal antibodies or siRNAs inhibited the receptor's function and prevented myeloma cell lysis.
Clinical trials are ongoing to determine a correlation with the number and function of NKG2D+CD3+CD8+ T cells and clinical outcomes in transplanted myeloma patients, including lymphocyte recovery following transplant and overall survival.