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Date of Award

Spring 5-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

A robust long-term antibody response is a desirable outcome of vaccination or infection because it confers onto the host the specific protection against the pathogen for an extended period of time. However, the molecular basis of such long-lasting antibody protection is unknown. In my dissertation, we demonstrated that ZBTB20, a BTB-ZF molecule, is a critical regulator of long-term antibody responses induced by alum-adjuvanted immunization. The expression levels of this factor progressively increase as differentiating B cells become more committed to the long-lived plasma cell fate. ZBTB20-deficient long-term antibody responses displayed significantly reduced titers relative to wild-type while acute responses were normal. We demonstrated that ZBTB20 is a B cell-intrinsic molecule critical for the maintenance of long-term antibody responses and for the persistence of terminally differentiated bone marrow plasma cells. The ZBTB20-deficient germinal center reaction and affinity maturation occurred normally. Additionally, ZBTB20-deficient switched memory B cells were also formed at normal frequency, as were splenic short-lived plasmablasts. These results suggest that ZBTB20 is specifically crucial in the post-germinal center B cells chosen for the plasma cell fate. Single-cell qPCR analysis revealed that ZBTB20-deficient germinal center-derived bone marrow plasmablasts express lower levels of MCL1 compared to wild-type ones, suggesting a defect in survival fitness without ZBTB20. Interestingly, the use of TLR2 and TLR4 ligands as adjuvants bypassed the requirement for ZBTB20 and MCL1 in maintaining long-term antibody responses, suggesting that TLR ligand adjuvants induce alternative pathways. Our findings demonstrate that germinal center-derived long lived plasma cells have adjuvant-specific pathways to maintain survival. Moreover, our data highlight the potential benefit of formulating combined adjuvants in vaccines to minimize variable performance of traditional single-adjuvant vaccines due to genetic heterogeneity in adjuvant-specific plasma cell programs. Furthermore, we identified ZBTB32, another BTB-ZF family member, as a factor exclusively expressed in CD80+CCR6+ switched memory B cells. Our preliminary data demonstrated that, while the ZBTB32-deficient primary B cell response is normal, the ZBTB32-deficient recall response is more robust than wild type due to more persistent memory B cell-derived plasma cells. Thus, my dissertation highlights the significance of the BTB-ZF family in the regulation of the long-term antibody response, just as its importance in many other aspects of the immune system.

Language

English (en)

Chair and Committee

Deepta Bhattacharya

Committee Members

Eugene Oltz, Kenneth Murphy, Marco Colonna, Michael Diamond

Comments

Permanent URL: https://doi.org/10.7936/K7X0656N

Available for download on Wednesday, May 15, 2115

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