PNAS, 27 April, 2021, DOI：https://doi.org/10.1073/pnas.2019798118

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

Xinwen Lin, Trix Twelkmeyer, Danming Zhu, Li Zhang, Yang Zhao,  Chao Zhang,  Yoichiro Iwakura,  Guangxun Meng, Zhaolin Hua, Bingyu Yan, William J. Liu, Zhongguang Luo, Sitang Gong, Hairong Chen, Shuran Li, Baidong Hou, and Hong Tang

Abstract

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, 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 T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the 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. In humans, a unique polymorphism in the 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 nonresponders.

Article link：https://www.pnas.org/content/118/17/e2019798118