ORCID

http://orcid.org/0000-0001-7837-2881

Date of Award

Winter 12-15-2019

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

Over the course of an effective immune response to an infection, two distinct B cell populations are generated to provide protection against reinfection, long-lived plasma cells (LLPCs) and memory B cells (MBCs). LLPCs and MBCs originate from germinal center (GC) B cells that have undergone B cell receptor (BCR) affinity maturation through iterative rounds of somatic hypermutation, proliferation, and selection. Thus, LLPCs and MBCs can bind to their antigen with higher affinity than their naïve B cell precursors. LLPCs constitutively secrete antibodies and can provide sterilizing immunity that pre-exists subsequent infections. MBCs, on the other hand, are quiescent and provide protection only after being re-activated. Re-activation of MBCs can result either in the re-initiation of GC reactions to mold and affinity mature BCRs toward new specificities or in the differentiation into plasma cells. However, the likelihood of re-activating MBCs in the presence of pre-existing serum antibodies secreted by LLPCs is low. Thus, the etiological role of MBCs is not well defined. We previously showed that MBCs are capable of recognizing pathogen escape mutants that have evaded serum neutralization by antibodies secreted from LLPCs, though it is unclear the breadth of diverse antigens recognized by MBCs.Here, we demonstrate that the diversity of MBCs extends to recognizing heterologous antigens. Using mouse models of sequential heterologous flavivirus vaccinations and activation induced cytidine deaminase conditional knockout mice in which affinity maturation is ablated, we observed that MBCs respond to heterologous antigens without further affinity maturation and remodeling of their BCRs. Instead, MBCs respond by directly differentiating into plasma cells to secrete antibodies, some of which are neutralizing, targeting the secondary pathogen. Thus, the diversity of MBCs generated after a primary response dictates the response to subsequent heterologous challenges. Mechanistically, this diversity results from the continued, active recruitment of low affinity germinal center B cells into the MBC pool.Given the different roles of LLPCs and MBCs upon secondary challenge by either a homologous or heterologous pathogen, understanding the durability of LLPC and MBC recall responses can provide insights on how to modulate length of responses. We previously showed that two members of the Broad complex, tramtrack, bric-a-brac-poxvirus, and zinc finger (BTB-POZ) family of transcription factors, ZBTB20 and ZBTB32, regulate distinct aspects of B cell memory responses. ZBTB20 regulates adjuvant-dependent survival of long-lived plasma cells, while ZBTB32 regulates the durability of recall response. Although the mechanisms of how ZBTB20 and ZBTB32 regulate responses is unclear, the N-terminal BTB-POZ domain likely recruits transcriptional repressors to different areas of DNA binding mediated by the C-terminal zinc finger domains. Thus, we hypothesized that ZBTB38, another member of the BTB-POZ family, may also regulate B cell responses. Using a mouse model in which ZBTB38 is deleted in hematopoietic cells, we demonstrate that ZBTB38 is dispensable for both primary and recall responses to a hapten immunogen.Taken together, we propose that the MBC diversity after a primary response is generated by the continued, but active, selection of low affinity germinal center B cells into the MBC pool, and that this diversity is directly utilized upon secondary challenges without further affinity maturation. In addition, both the primary B cell and MBC recall responses do not require expression of ZBTB38. Further work needs to be done defining the recall responses of MBCs to live viruses and cues that promote the continuous selection of low-affinity GC B cells into the MBC compartment.

Language

English (en)

Chair and Committee

Deepta Bhattacharya Paul Allen

Committee Members

Michael S. Diamond, Daved H. Fremont, Sharon C. Morley,

Comments

Permanent URL: https://doi.org/10.7936/9866-kk98

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