Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution.
B cell antigen receptor (BCR) cross-linking promotes proliferation and survival of mature B cells. Phosphoinositide-3-kinase-mediated down-regulation of pro-apoptotic and anti-mitogenic genes such as the Foxo family of transcription factors is an important component of this process. Previously, we demonstrated that BCR signaling decreases expression of transcripts for Foxo1, Foxo3 and Foxo4. We now show that BCR-induced down-regulation of Foxo3 and Foxo4 mRNA expression occurs via distinct mechanisms from those established for Foxo1. While Foxo1, Foxo3 and Foxo4 bind the same DNA sequence, the differential control of their expression upon B cell activation suggests that they may have unique functions in the B lineage. To begin to address this issue, we evaluated B cell development and function in Foxo3-/- mice. No effect of Foxo3 deficiency was observed with respect to the following parameters in the splenic B cell compartment: sub-population distribution, proliferation, in vitro differentiation and expression of the Foxo target genes cyclin G2 and B cell translocation gene 1. However, Foxo3-/- mice demonstrated increased basal levels of IgG2a, IgG3 and IgA. A significant reduction in pre-B cell numbers was also observed in Foxo3-/- bone marrow. Finally, recirculating B cells in the bone marrow and peripheral blood were decreased in Foxo3-/- mice, perhaps due to lower than normal expression of receptor for sphingosine-1 phosphate, which mediates egress from lymphoid organs. Thus, Foxo3 makes a unique contribution to B cell development, B cell localization and control of Ig levels.
Hinman
Rochelle M
RM
Department of Internal Medicine, Division of Rheumatology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Nichols
Whitney A
WA
Diaz
Tracy M
TM
Gallardo
Teresa D
TD
Castrillon
Diego H
DH
Satterthwaite
Anne B
AB
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D002070:Butadienes / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D056766:Cyclin G1; D056767:Cyclin G2; D016213:Cyclins / Q000276:immunology / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000187:drug effects / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
D000888:Antibodies, Anti-Idiotypic; D002070:Butadienes; D018797:Cell Cycle Proteins; D002867:Chromones; D056766:Cyclin G1; D056767:Cyclin G2; D016213:Cyclins; D016572:Cyclosporine; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D015851:Interleukin-7; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D011947:Receptors, Antigen, B-Cell; C534703:Ccng1 protein, mouse; C474033:FoxO3 protein, mouse; C525394:FoxO4 protein, mouse; C467200:Foxo1 protein, mouse; C113580:U 0126; C044203:anti-IgM; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one