Thesis (Ph.D.)--University of Washington, 2023Germinal center (GC)-derived memory B cells (MBCs) play a pivotal role in humoral immunity by differentiating into protective antibody-secreting cells upon re-infection. Despite extensive research focused on GC formation and the cellular interactions occurring within the GC microenvironment, the precise signals which regulate MBC selection and exit remain incompletely understood. In these studies, we focus on the role of interleukin-4 (IL-4) in the GC using murine blood-stage Plasmodium infections as a model of for a type 1 immune response. Our findings demonstrate that IL-4 signaling can trigger the selection and exit of GC B cells by modulating the expression of BCL6, the primary transcription factor within the GC. Specifically, we show that IL-4 induces negative autoregulation of BCL6, leading to a loss in expression of this anti-apoptotic factor within GC B cells. Consequently, in the presence of excess IL-4, there is increased GC B cell death and a loss of selection stringency. Furthermore, we demonstrate that in the absence of IL-4-mediated downregulation of BCL6, B cells with lower affinity can persist within the GC and contribute to the MBC pool. This observation highlights the critical role of IL-4-mediated downregulation of BCL6 in maintaining selection stringency and affinity maturation within the MBC population. By elucidating the role of IL-4 in modulating the fate of GC B cells, we have demonstrated the significance of IL-4 signaling in shaping the dynamics of the GC selection and subsequent memory formation.
The importance of both GCs and memory formation are further underscored in chapter 3, in which we analyze the B cell response generated by both protein nanoparticle vaccines and by natural infection with SARS-CoV-2. As the formation of class-switched MBCs and LLPCs are the primary correlate of protection for vaccination, our finding that a nanoparticle displaying the receptor binding domain of SARS-CoV-2 can elicit the formation of a robust GC with class-switched B cells was very promising for the future of nanoparticle vaccines.
Collectively, these findings offer novel insights into the mechanisms underlying MBC selection and affinity maturation within the GC. Through the identification of IL-4 as a negative regulator of BCL6 expression and its impact of GC B cell survival, our study advances the current understanding of how the immune system maintains an optimal balance between selection stringency and the generation of diverse MBC populations. Further research in this area will likely explore additional signaling pathways and molecular players involved in the complex network of interactions governing GC-derived MBC selection, and ultimately will contribute to the development of strategies aimed at enhancing immune responses and vaccine efficacy
