PTEN negatively regulates natural killer cell function against leukemic target cells in a transgenic mouse model
Year: 2013
Type: dissertation
Abstract: Human natural killer (NK) cells are CD56+CD3- large granular lymphocytes that represent the body’s first line of defense against virally infected and malignantly transformed cells. In order to distinguish harmful cells from healthy cells, the NK cell integrates signaling input from a variety of activating and inhibitory receptors expressed along its surface. How these signals ultimately regulate NK cell function, however, is not well defined. Here we present a novel role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) in the negative regulation of NK cell activity. Primary NK cells isolated from transgenic mice overexpressing PTEN (Super-PTEN) displayed decreased cytotoxic activity against leukemic target cells in culture. Additionally, Super-PTEN NK cells exhibited reduced interferon-gamma (IFN-γ) production upon IL-12 and IL-18 co-stimulation. These effects on the regulation of NK cell activity seem to be mediated at least in part by PTEN’s direct effects upon PI3K signaling as suggested by AKT and ERK activation levels. Super-PTEN NK cells showed no difference in NK receptor expression nor any changes in NK cell development as evidenced by CD27 and CD11b expression. In addition, lentiviral overexpression of PTEN in human NK cells recapitulated the effects of murine NK cell overexpression. Collectively, these results suggest that PTEN negatively regulates NK cell function via its direct effects upon PI3K signaling, but does not affect the development of mature NK cells. These findings may have clinical relevance for targeting PTEN in the treatment of cancer and other proliferative diseases.
Author: Alex S. Hartlage
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W593790762