Shaping mucosal immunity through IκBζ-dependent lymph node stromal cell activation 2783

Abstract Description Fibroblastic reticular cells (FRCs) are the stromal organizers of lymph node (LN) architecture and are increasingly found to regulate all stages of immune responses. Our previous study showed that IL-17-dependent metabolic reprograming of FRC during LN inflammation was critical not only for FRC proliferation and survival but also for B cell germinal centers (GC) and antibody production. However, Th17 cells themselves were not impaired. Our in vitro RNAseq and knockdown assays suggested the NF-κB co-activator IκBζ as a key mediator of IL-17 response in FRC. To test the role of IκBζ in shaping mucosal immunity, we employed FRC-restricted IκBζ deletion (Ccl19Cre-Nfkbizfl/fl) and challenged these mice with Citrobacter rodentium infection and oral vaccination. FRC expression of IκBζ was required for FRC expansion in inflamed LN of challenged mice, and for optimal GC and antibody responses. Infected mice showed enhanced C. rodentium fecal shedding and delayed clearance, similar to FRC-specific IL-17RA deletion. Unexpectedly, FRC-specific deletion of IκBζ additionally caused reduced T cell activation and selectively reduced T helper 17 cells and T follicular helper cells. In conclusion, these data show that IκBζ expression is a key mediator of FRC responses promoting adaptive immunity in the gut and associated lymphoid tissues. Funding Sources NIH AI70773, AI44229 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)