The Role of Foxo Transcription Factors in B Cell Development and Activation
dc.contributor.advisor | Satterthwaite, Anne B. | en |
dc.creator | Hinman, Rochelle Marie | en |
dc.date.accessioned | 2011-09-30T18:52:39Z | |
dc.date.available | 2012-12-01T18:52:39Z | |
dc.date.issued | 2010-01-12 | |
dc.description.abstract | A functional immune system depends on a diverse, self tolerant B cell repertoire. Mature B cells distributed throughout secondary lymphoid organs respond to antigenic stimuli by dividing and differentiating into plasma cells and other effector cell types. Signaling from the B cell receptor (BCR) plays a critical role at several points during this developmental process. Cell survival, proliferation, differentiation, death, anergy, and receptor editing may occur in response to BCR stimulation. A variety of factors, including signal strength and duration, cytokine presence, and co-stimulation determine the ultimate B cell fate. In this thesis, the roles Foxo transcription factors play in maintaining B cell homeostasis will be explored. Foxo1, Foxo3, and Foxo4 have both anti-mitogenic and pro-apoptotic properties. The transcription factors are posttranslationally controlled via Akt. When a mature B lymphocyte is stimulated through the BCR, Akt-mediated phosphorylation of Foxos results in their exclusion from the nucleus. In the absence of Foxo nuclear activity, the B cell progresses into the cell cycle. We have discovered a second PI3K-dependent means of control for Foxos, at the level of mRNA expression. Downstream of the BCR, this means of control is unique and functionally relevant. Mature B cells proliferating in response to anti-IgM downregulate Foxo mRNA expression. This is via activation of the PI3K/Btk/BLNK/PLC-gamma2 pathway. Conversely, Foxo mRNA expression is upregulated in immature B cells, both when the tonic/basal signal through the BCR is disrupted and when the BCR is engaged with anti-IgM. Overexpression of Foxo3 mRNA in an immature B cell line promotes anti- IgM induced apoptosis. Primary immature B cells from Foxo3-/- mice have decreased apoptotic response to BCR crosslinking. Thus, at the immature stage of development our work has revealed a potential role for Foxo3 in promoting clonal deletion. Foxo3-/- mice also have reduced frequencies of pre-B and mature recirculating B cells in the blood and bone marrow. The mice demonstrate increased basal levels of IgG2a, IgG3, and IgA. Thus, Foxo3 deficiency affects numerous aspects of B cell development. | en |
dc.identifier.oclc | 761079609 | |
dc.identifier.uri | https://hdl.handle.net/2152.5/901 | |
dc.language.iso | en | en |
dc.subject | B-Lymphocyte Subsets | en |
dc.subject | Forkhead Transcription Factors | en |
dc.subject | Homeostasis | en |
dc.title | The Role of Foxo Transcription Factors in B Cell Development and Activation | en |
dc.type | Thesis | en |
dc.type.material | Text | en |
thesis.degree.department | Graduate School of Biomedical Sciences | en |
thesis.degree.discipline | Immunology | en |
thesis.degree.grantor | UT Southwestern Medical Center | en |
thesis.degree.level | Doctoral | en |
thesis.degree.name | Doctor of Philosophy | en |
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