TY - JOUR
T1 - Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell sub-population distribution
AU - Hinman, Rochelle M.
AU - Nichols, Whitney A.
AU - Diaz, Tracy M.
AU - Gallardo, Teresa D.
AU - Castrillon, Diego H.
AU - Satterthwaite, Anne B.
N1 - Funding Information:
National Institutes of Health Grants (AI049248 to A.B.S., 1K26RR024196 to D.H.C., T32 AI 005284-28 to R.M.H.); University of Texas Southwestern Summer Undergraduate Research Fellowship Program to W.A.N.; Southwestern Medical Foundation Scholarship in Biomedical Research to A.B.S.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - B cells
KW - Cell activation
KW - Knockout mice
KW - Signal transduction
KW - Transcription factors
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U2 - 10.1093/intimm/dxp049
DO - 10.1093/intimm/dxp049
M3 - Article
C2 - 19502585
AN - SCOPUS:67649838590
SN - 0953-8178
VL - 21
SP - 831
EP - 842
JO - International Immunology
JF - International Immunology
IS - 7
ER -