Altered splenic B cell subset development in mice lacking phosphoinositide 3-kinase p85alpha.
The signaling enzyme phosphoinositide 3-kinase (PI3K) is activated following B cell receptor (BCR) engagement and by many other receptors on B lymphocytes. Mice lacking p85alpha, the predominant PI3K regulatory isoform, exhibit defects in B cell development and activation that are grossly similar to those found in mice lacking Bruton's tyrosine kinase (Btk) and other critical signaling molecules. However, a detailed analysis of splenic B cell subsets in p85alpha-deficient mice has not been reported. Here we show that these mice are deficient in four major B cell subsets: transitional-1, transitional-2, follicular and marginal zone. These defects are distinct from those observed in Xid mice that express a mutant Btk unable to interact with PI3K lipid products. Moreover, mice with both genetic lesions exhibit even greater impairment in B cell development. Finally, we show that transgenic expression of the anti-apoptotic protein Bcl-2 in p85alpha-deficient mice restores the transitional B cell subsets but not the marginal zone subset, and produces a follicular population with an aberrant phenotype. These findings establish a role for PI3K-p85alpha in differentiation of both follicular and marginal zone B cells, and suggest that these functions are required not solely for the propagation of anti-apoptotic signals.
Donahue
Amber C
AC
Center for Immunology and Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA.
Hess
Kristen L
KL
Ng
Kwan L
KL
Fruman
David A
DA
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D017209:Apoptosis; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000166:cytology / Q000276:immunology*; D019076:Transgenes / Q000235:genetics / Q000502:physiology
D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse