TY - JOUR
T1 - Influenza virus infection expands the breadth of antibody responses through IL-4 signalling in B cells
AU - Miyauchi, Kosuke
AU - Adachi, Yu
AU - Tonouchi, Keisuke
AU - Yajima, Taiki
AU - Harada, Yasuyo
AU - Fukuyama, Hidehiro
AU - Deno, Senka
AU - Iwakura, Yoichiro
AU - Yoshimura, Akihiko
AU - Hasegawa, Hideki
AU - Yugi, Katsuyuki
AU - Fujii, Shin ichiro
AU - Ohara, Osamu
AU - Takahashi, Yoshimasa
AU - Kubo, Masato
N1 - Funding Information:
We thank Dr. Manfred K. for providing Il4−/− and Il6−/− mice. We thank Dr. Brom-bacher F. for providing Il4ra−/− and Il4raf/f mice. Tmprss2−/− mice, Gata3f/f ert2cre mice, and Verigem mice were kindly gifted from Dr. Takeda, M., Dr. Zhu, J., and Dr. Allen C. We thank Dr. T. Kitami, S. Ki and Y. Suzuki, for technical support and animal maintenance. We thank Dr. P. Burrows for his helpful comments on the manuscript. This work was supported by a Grant-in-Aid for Scientific Research (B) (19H03491) to M.K. Scientific Research (C) (18K06647) to K.M. JSPS KAKENHI (S) (JP17H06175) and AMED-CREST (JP20GM1110009) grants to A.Y. JSPS KAKENHI (JP19K17656) and AMED (JP20JK0108141) grants to Y.T. This work was supported by Mochida Memorial Foundation for Medical and Pharmaceutical Research, and Daiichi-Sankyo Foundation of Life Science.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-24090-z
DO - 10.1038/s41467-021-24090-z
M3 - Article
C2 - 34145279
AN - SCOPUS:85108149462
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3789
ER -
