Advisory Committee Chair
Frances E Lund
Advisory Committee Members
Mary-Ann Bjornsti
Randy Q Cron
John F Kearney
Chander Raman
Casey T Weaver
Document Type
Dissertation
Date of Award
2017
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
The transcription factor T-bet regulates the epigenetic programming and differentiation of cytotoxic and helper T (Th) cells. Several studies recently identified T-bet expression in B cells after stimulation with TLR7 or interferon alpha or gamma. T-bet controls isotype switching to IgG2a in B cells; however, the mechanism by which T-bet exerts this effect and whether T-bet regulates fate decision beyond isotype choice is not clear. When activated by interferon gamma-producing Th cells, B cells rapidly upregulate T-bet and undergo T-bet dependent changes in chromatin accessibility and wide-scale transcriptional reprogramming. T-bet controls expression of the core transcription factors required for antibody secreting cell (ASC) development in both in vitro Th-activated B cells and in vivo in virus-specific germinal center B cells. Analogous to its role in cytotoxic T cells, T-bet-/- B cells exhibit normal short-live plasmablast differentiation, but terminally differentiated long-lived plasma cells (LLPC) were severely hampered. Interestingly, T-bet was required for formation of both IgG1+ and IgG2c+, but not IgG2b+ LLPC, suggesting an alternate pathway mediates IgG2b CSR. Expression of genes required for plasma cell differentiation was controlled by T-bet in germinal center B cells. T-bet expression in memory B cells was required for formation of plasmablasts after challenge, though it was not required for memory cell formation. Moreover, T-bet+ B lineage cells drive autoantibody-mediated disease in a TLR7-dependent model of SLE, indicating that T-bet+ SLE B cells are pathogenic rather than exhausted. Collectively, these data show that T-bet acts as master epigenetic regulator of both primary and secondary virus-specific ASC responses and critically mediates autoreactive plasma cell differentiation in a murine model of systemic lupus erythematous.
Recommended Citation
Stone, Sara Stone, "A Novel Role For T-Bet And Ifng In Directing B Cell Differentiation" (2017). All ETDs from UAB. 3050.
https://digitalcommons.library.uab.edu/etd-collection/3050