Defining molecular adjuvant effects on human B cell subsets

Abstract

Recent advances in vaccine development include the incorporation of novel adjuvants to increase vaccine immunogenicity and efficacy. Pattern recognition receptor (PRR) ligands are of particular interest as vaccine adjuvants. During early childhood, the B cell compartment contains a high frequency of immature, transitional B cells. This prominent transitional B cell population may encounter PRR ligands during immunization; however, the response of human transitional B cells to these stimuli remains largely unknown. The goal of this dissertation work was to evaluate the capacity of PRR ligands to drive transitional B cells to mature into follicular or marginal zone B cells by assessing transitional B cell maturation and evaluating the transcriptome of mature B cell subsets. This work determined that PRR ligands can drive the phenotypic maturation of human transitional B cells as measured by CD23 expression and Rhodamine 123 retention. In vitro transitional B cell maturation resulted in the generation of both Fo-like and MZ-like B cells as determined by surface phenotype. Additionally, select PRR ligands induced gene expression changes in transitional B cells similar to mature B cells. We analyzed human tonsil follicular and marginal zone-like B cell transcriptomes to identify several genes uniquely associated with either cell fate decision and assessed the expression of some of these genes in our in vitro transitional B cell maturation model. To the best of our knowledge, this is the first study to examine the differential effect of various PRR ligands on the maturation of human transitional B cells into mature, naïve B cells and to examine the follicular versus marginal zone B cell fate decision. The rational design of vaccine adjuvants that take into consideration the effect of PRR ligands on B cell maturation and differentiation may lead to new strategies to improve the immunogenicity and efficacy of childhood vaccines.