1. ¹Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA
2. ²Department of Cancer Biology, University of California, Los Angeles, CA 92129, USA
3. ³Hunter College, City University of New York, New York, NY 10021, USA
4. ⁴Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA

Correspondence: Shuhua Cheng, 515 East 71 Street, S-222 New York, NY 10021, USA Tel: +1-212-746-4409; Fax: +1-212-746-8167 E-mail: shc2019@med.cornell.edu; Hsiou-Chi Liou, 515 East 71 Street, S-210 New York, NY 10021, USA Tel: +212-746-4451; Fax: +212-746-8167 E-mail: hcliou@med.cornell.edu

Received 26 June 2008; Revised 10 July 2008; Accepted 10 July 2008.

Abstract

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.