Maturation and maintenance of the germinal center niche

About This Grant

Project Summary/Abstract Follicular dendritic cells (FDCs) are specialized stromal cells that form clusters in B cell follicles of peripheral lymphoid organs. These FDC clusters demarcate the light zone of the germinal center (GC), where B cells that have undergone somatic hypermutation of their B cell receptor (BCR) genes are selected for increased BCR affinity with the help from T follicular helper (Tfh) cells. FDCs not only provide structural support to recruit GC B cells and Tfh cells, but also retain native antigens for extended periods and present them to B cells to facilitate B cell selection in GCs. Despite their essential role in GC reactions, little is known about the origin and maturation process of FDCs, or the mechanisms controlling the formation and maintenance of FDC clusters. This proposal is based on our previous findings that FDCs in the spleen form developmentally predetermined clusters. While the number of splenic FDC clusters remains constant irrespective of germ-free, immunization or chronic inflammatory conditions, FDCs can undergo expansion and morphological changes during GC reactions. We hypothesize that FDC clusters are maintained by slow FDC replenishment under steady state, with turnover rates increasing in response to inflammation. At the molecular level, we propose that TNF is essential not only for FDC development but also for maintaining FDC identify by regulating the gene program of mature FDCs. Here, we propose to (1) determine FDC longevity and turnover in young and aged mice at steady state, post-immunization, and under chronic lupus inflammatory conditions, and (2) determine the molecular mechanisms underlying the maintenance of FDC clusters. Our exploratory studies will establish a foundation for further investigation into TNF-mediated molecular pathways that sustain functional FDC clusters. These endeavors will not only expand our understanding of the mechanisms regulating GC reactions but also have clinical implications for improving vaccination efficacy and developing interventions for antibody-mediated autoimmunity.