A Germinal Center Immunomodulator: The CTA1-DD Adjuvant Acts on Follicular Dendritic Cells and Potentiates Follicular T Helper Cell Functions

The non-toxic CTA1-DD adjuvant, ADP-ribosylates Gsα in the cell membrane of targeted cells and strongly promotes large and numerous germinal centers (GC) following mucosal or systemic administration. This leads to greatly enhanced antibody responses and memory B cell development. In dissecting the mechanism of activation, we observed that the enhanced GC reaction was critically dependent on activation of complement and subsequent binding to complement receptor 2 on follicular dendritic cells (FDC). Therefore, we developed a mouse model expressing the GFP marker gene under the CD21 promotor to detect the FDC network, which allowed us to analyse the impact of CTA1-DD on GC formation in greater detail. FDC and other stromal cells produce chemokines and molecular binding partners, and in this way promote interactions between B cells and follicular T helper cells (Tfh). After sorting stromal cells populations we conducted a gene-expression analysis. We found that, CTA1-DD induced transcriptional changes in FDC and increased GC responses in adult and infant mice. Thus, CTA1-DD modulated the follicular environment and appeared to circumvent the intrinsic GC B cell and Tfh impairment seen in infants. We, therefore, conclude that cell targeted CTA1-DD adjuvant augments the generation of Tfh and promotes FDC functions to potentiate the GC reaction not only in adults, but also in infants. We think this could be exploited to improve vaccine safety and efficacy in adults as well as young children.