Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin

HBV vaccine is composed of surface antigen (HBsAg) that spontaneously assembles into subvirus particles. Factors that impede its humoral immunity in 5-10% of vaccinees remain elusive. Herein we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra inhibited Tfh cell expansion and subsequent GC dependent humoral immunity, resulting in significantly weakened protection against HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages (MSM). In humans, a unique polymorphism in RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine non-responders. Overall design: mRNA profiles of wt mouse lymph node and spleen derived CD169+ macrophages 2h after HBsAg and ova immunization