BCR-mediated apoptosis associated with negative selection of immature B cells is selectively dependent on Pten.
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.
Cheng
Shuhua
S
Department of Medicine, Division of Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA. shc2019@med.cornell.edu
Hsia
Constance Yu
CY
Feng
Biao
B
Liou
Mei-Ling
ML
Fang
Xiaoying
X
Pandolfi
Pier Paolo
PP
Liou
Hsiou-Chi
HC
D000818:Animals; D017209:Apoptosis; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000201:enzymology* / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*
D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase