Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex.
Many receptor and nonreceptor tyrosine kinases activate phosphoinositide 3-kinases (PI3Ks). To assess the role of the delta isoform of the p110 catalytic subunit of PI3Ks, we derived enzyme-deficient mice. The mice are viable but have decreased numbers of mature B cells, a block in pro-B-cell differentiation, and a B1 B-cell deficiency. Both immunoglobulin M receptor-induced Ca(2+) flux and proliferation in response to B-cell mitogens are attenuated. Immunoglobulin levels are decreased substantially. The ability to respond to T-cell-independent antigens is markedly reduced, and the ability to respond to T-cell-dependent antigens is completely eliminated. Germinal center formation in the spleen in response to antigen stimulation is disrupted. These results define a nonredundant signaling pathway(s) utilizing the delta isoform of p110 PI3K for the development and function of B cells.
Jou
Shiann-Tarng
ST
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Carpino
Nick
N
Takahashi
Yutaka
Y
Piekorz
Roland
R
Chao
Jyh-Rong
JR
Carpino
Neena
N
Wang
Demin
D
Ihle
James N
JN
D000818:Animals; D000955:Antigens, T-Independent / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D005434:Flow Cytometry; D018390:Gene Targeting; D018858:Germinal Center / Q000166:cytology / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology
D000955:Antigens, T-Independent; D007136:Immunoglobulins; D046911:Macromolecular Substances; D011947:Receptors, Antigen, B-Cell; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; C421683:Pik3cd protein, mouse; D002118:Calcium