Human Primary NK Cells from Humanized BLT-IL15 Mice Show Superior
Expansion and Cytotoxicity in Comparison with Humanized BLT-mice Using
Membrane Bound IL21-modified 721.221 Feeder Cell Expansion System
Abstract
Background: Natural Killer (NK) cells play a critical role in host
defense. Studying human NK immunobiology is mainly focused on using in
vitro assays with limited NK cells from peripheral blood. It is
challenging to study human NK cell biology in vivo due to potential
ethical issues in human study and the lack of suitable animal models.
Developing a suitable animal model to study human NK cell biology in
vivo is critical to support NK-based clinical immunotherapy. Results:
Here, we develop a novel method to study human NK cells in vivo by using
hu-BLT (humanized bone marrow-liver-thymus) mice that constitutively
express human IL-15 (henceforth, hu-BLT-IL15). We also compare human NK
cells between hu-BLT-IL15 and hu-BLT mice without IL-15 expression by a
newly developed approach for the rapid propagating of primary human NK
cells from various sources (including peripheral blood, spleen, and bone
marrow). NK cells from hu-BLT-IL15 show superior number, purity, and
cytotoxicity (including natural cytotoxicity and antibody-dependent
cellular cytotoxicity [ADCC]), compared with NK cells from hu-BLT.
Unexpectedly, we also identify a significantly increased percentage of
NK-like T cells (CD3+ CD16+ CD56+) from hu-BLT-IL15, indicating that
IL-15 signaling enhances both NK and NKT cell development. Conclusions:
A better understanding of the immunobiology of the NK-like T cells in
the hu-BLT-IL15 mouse model may provide critical information for
determining the clinical value of these cells in predicting disease
progression. Thus, we propose that the hu-BLT-IL15 mouse model in
combination with the 721.221-mIL21 feeder cell expansion system can
serve as a superior model to study human NK and NK-like T cells in
comparison with hu-BLT.