Influenza virus infection expands the breadth of antibody responses through IL-4 signalling in B cells

Kosuke Miyauchi,Yoichiro Iwakura,Yasuyo Harada,Senka Deno,Yu Adachi,Osamu Ohara,Hidehiro Fukuyama,Katsuyuki Yugi,Shin-Ichiro Fujii,Taiki Yajima,Akihiko Yoshimura,Masato Kubo,Keisuke Tonouchi,Yoshimasa Takahashi,Hideki Hasegawa

doi:10.1038/s41467-021-24090-z

Abstract

Influenza viruses are a major public health problem. Vaccines are the best available countermeasure to induce effective immunity against infection with seasonal influenza viruses; however, the breadth of antibody responses in infection versus vaccination is quite different. Here, we show that nasal infection controls two sequential processes to induce neutralizing IgG antibodies recognizing the hemagglutinin (HA) of heterotypic strains. The first is viral replication in the lung, which facilitates exposure of shared epitopes that are otherwise hidden from the immune system. The second process is the germinal center (GC) response, in particular, IL-4 derived from follicular helper T cells has an essential role in the expansion of rare GC-B cells recognizing the shared epitopes. Therefore, the combination of exposure of the shared epitopes and efficient proliferation of GC-B cells is critical for generating broadly-protective antibodies. These observations provide insight into mechanisms promoting broad protection from virus infection.

Highlights

Influenza viruses are a major public health problem
Broadly neutralizing Abs have been cloned from memory B cells of infected individuals and these antibodies mainly target the region of the HA stalk domain, which is highly conserved among group 1 and group 2 influenza A viruses, and heavy-chain variable (VH) region genes encoding these antibodies are heavily mutated[18,19]. These results strongly suggest that somatic hypermutation (SHM) of immunoglobulin (Ig) genes in the germinal center (GC) is critical for highaffinity binding to heterosubtypic HA antigenic determinants[13]
These results indicated that protective immunity induced by initial priming with live A/Narita/1/2009 extended the breadth of protection to include heterotypic H1N1 influenza virus strains

Summary

Introduction

Influenza viruses are a major public health problem. Vaccines are the best available countermeasure to induce effective immunity against infection with seasonal influenza viruses; the breadth of antibody responses in infection versus vaccination is quite different. The combination of exposure of the shared epitopes and efficient proliferation of GC-B cells is critical for generating broadlyprotective antibodies These observations provide insight into mechanisms promoting broad protection from virus infection. The inactivated vaccine predominantly induces antibodies recognizing the globular head domain of HA, and these antibodies generally correlate with the GC response[11,12,13]. These regions are highly susceptible to antigenic drift and the inactivated vaccine is sensitive to these antigenic changes

Methods

Results

Conclusion