Volume 19, No 2, Feb 2009
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 19 Issue 2, February 2009: 196-207
ORIGINAL ARTICLES
BCR-mediated apoptosis associated with negative selection of immature B cells is selectively dependent on Pten
Shuhua Cheng1, Constance Yu Hsia1, Biao Feng1, Mei-Ling Liou2, Xiaoying Fang3, Pier Paolo Pandolfi4 and Hsiou-Chi Liou1
1Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
2Department of Cancer Biology, University of California, Los Angeles, CA 92129, USA
3Hunter College, City University of New York, New York, NY 10021, USA
4Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
Correspondence: Shuhua Cheng, Hsiou-Chi Liou,(shc2019@med.cornell.edu; hcliou@med.cornell.edu)
The molecular basis of B cell receptor (BCR)-induced apoptosis during the negative selection of immature B cells is largely unknown. We use transitional immature B cells that are highly susceptible to BCR-induced apoptosis to show that Pten is selectively required for BCR-mediated initiation of the mitochondrial death pathway. Specifically, deleting Pten, but not other pro-apoptotic molecules, abrogates BCR-elicited apoptosis and improves viability in wild-type immature B cells. We further identify a physiologically and significantly higher intracellular Pten level in immature B cells, as compared to mature B cells, which is responsible for low AKT activity and the propensity towards death in immature B cells. Restoration of AKT activity using a constitutive form of AKT or reduction of Pten to a level comparable with that seen in mature B cells rescues immature B cells from BCR-induced apoptosis. Thus, we provide evidence that Pten is an essential mediator of BCR-induced cell death, and that differential regulation of intracellular Pten levels determines whether BCR ligation promotes cell death or survival. Our findings provide a valuable insight into the mechanisms underlying negative selection and clonal deletion of immature B cells.
Cell Research (2009) 19:196-207. doi: 10.1038/cr.2008.284; published online 9 September 2008
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