Homeostatic Regulation of T Follicular Helper and Antibody Response to Particle Antigens by IL-1Ra of Medullary Sinus Macrophage Origin

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Apr 20

PMID 33875594

Authors

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

Hong Tang

Affiliations

Soon will be listed here.

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.

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