REQUIREMENTS FOR MEMORY B CELL AND LONG LIVED PLASMA CELL DEVELOPMENT DURING ADAPTIVE IMMUNE RESPONSES AND STAPHYLOCOCCUS AUREUS INFECTION Public Deposited

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  • March 19, 2019
Creator
  • Keener, Amanda
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Memory B cells and plasma cells (PCs) are terminally differentiated B cells that contribute to recall responses vital for protection against infections. Formation of high affinity memory B cells requires cognate T cell help, somatic hypermutation and affinity maturation within germinal centers (GCs); however, the signals that commit B cells to the GC and the memory pool remain unclear. This work identifies IgG immune complexes (ICs), FcγRs, and BAFF as vital players in the GC response and formation of memory B cells. Early secretion of IgG lead to IC-FcγR interactions that induced dendritic cells to secrete BAFF, which in turn promoted Bcl-6 expression in activated B cells. Loss of FcγRIII, hematopoietic cell-derived BAFF, or blocking Ig-Fc regions all diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary antibody responses. This work highlights a key role for IC-FcγR interactions in B cell fate decisions. ICs may be targeted by pathogens known to disrupt adaptive immune responses, like Staphylococcus aureus. Infection with S. aureus does not induce long-lived protective immunity. Although vaccine studies in mice and humans support the role of antibodies in protecting against recurring infections, it is not clear whether memory B cells or long-lived plasma cells are formed after S. aureus infection. The activity of B cells in response to S. aureus is compromised by Protein A (SpA), a surface protein that interferes with IgG-FcγR interactions and opsonization of the bacteria, and induces polyclonal expansion of VhIII B cells. Using a SpA deletion mutant, we found that GCs, antibody responses, and memory B cell formation were unaffected by the presence of SpA. However, SpA drove an enhanced short-lived extrafollicular response and reduced the pool of long-lived bone marrow resident PCs that were derived from activated memory B cells. This led to a rapid decline in antigen-specific, class-switched antibody. Thus, failure to establish long-term protective antibody titers against S. aureus was not a consequence of diminished B cell memory formation, but a lack of long-term antibody maintenance.
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  • In Copyright
Advisor
  • Roubey, Robert
  • Matsushima, Glenn
  • Vilen, Barbara J.
  • Sarantopoulos, Stefanie
  • Richardson, Anthony
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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