The catalytic PI3K isoforms p110gamma and p110delta contribute to B cell development and maintenance, transformation, and proliferation.
Class I PI3K-dependent signaling regulates cell proliferation, differentiation, and survival. Analysis of gene-deficient mice revealed specific roles for the hematopoietically expressed PI3K catalytic subunits, p110gamma and p110delta, in development and function of T and B lymphocytes. However, the functional redundancy between these two PI3K isoforms in the B cell lineage remains unclear. Here, we demonstrate that p110delta and p110gamma are expressed in B cells at early developmental stages. Normal B cell differentiation requires both isoforms, as p110gamma/p110delta double deficiency causes an increased percentage of CD43(hi)/B220(+)/CD19(-) cells as compared with single deficiency. Interestingly, initial transformation efficiency of B cell precursors was strongly reduced in double-deficient cells following transformation by p185 bcr-abl or v-abl oncogenes as compared with single-deficient cells. The requirement of p110gamma and p110delta in B cell development is underlined by reduced splenic B cell numbers of p110gamma/p110delta double-deficient mice and of lethally irradiated wild-type mice reconstituted with double-deficient BM. Moreover, the peripheral maintenance of p110gamma/p110delta double-deficient T and B cells was highly impaired following adoptive transfer of double-deficient splenocytes into wild-type mice. Functionally, LPS stimulation of splenocytes revealed proliferation defects resulting in decreased survival of p110gamma/p110delta double-deficient B cells, which correlated with impaired induction of D-type cyclins and Bcl-X(L). Surprisingly, this was not observed when purified B cells were analyzed, indicating a contribution of likely cell-extrinsic factor(s) to the impaired proliferation of double-deficient B cells. Thus, we provide novel evidence that p110gamma and p110delta have overlapping and cell-extrinsic roles in the development, peripheral maintenance, and function of B cells.
Beer-Hammer
Sandra
S
1. Abteilung für Pharmakologie und Experimentelle Therapie, Klinikum der Eberhard-Karls-Universität Tübingen, Wilhelmstrasse 56, D-72074 Tübingen, Germany. sandra.beer-hammer@uni-tuebingen.de; Institute of Biochemistry and Molecular Biology II, University of Düsseldorf, Universitätsstrabetae 1, D-40225 Düsseldorf, Germany. E-mail: roland.piekorz@uni-duesseldorf.de.
Zebedin
Eva
E
von Holleben
Max
M
Alferink
Judith
J
Reis
Bernhard
B
Dresing
Philipp
P
Degrandi
Daniel
D
Scheu
Stefanie
S
Hirsch
Emilio
E
Sexl
Veronika
V
Pfeffer
Klaus
K
Nürnberg
Bernd
B
Piekorz
Roland P
RP
D000011:Abelson murine leukemia virus / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D005260:Female; D005434:Flow Cytometry; D016313:Genes, abl / Q000502:physiology; D007527:Isoenzymes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D007527:Isoenzymes; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse