Distinct germinal center selection at local sites shapes memory B cell response to viral escape.
Respiratory influenza virus infection induces cross-reactive memory B cells targeting invariant regions of viral escape mutants. However, cellular events dictating the cross-reactive memory B cell responses remain to be fully defined. Here, we demonstrated that lung-resident memory compartments at the site of infection, rather than those in secondary lymphoid organs, harbor elevated frequencies of cross-reactive B cells that mediate neutralizing antibody responses to viral escape. The elevated cross-reactivity in the lung memory compartments was correlated with high numbers of VH mutations and was dependent on a developmental pathway involving persistent germinal center (GC) responses. The persistent GC responses were focused in the infected lungs in association with prolonged persistence of the viral antigens. Moreover, the persistent lung GCs supported the exaggerated B cell proliferation and clonal selection for cross-reactive repertoires, which served as the predominant sites for the generation of cross-reactive memory progenitors. Thus, we identified the distinct GC selection at local sites as a key cellular event for cross-reactive memory B cell response to viral escape, a finding with important implications for developing broadly protective influenza vaccines.
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
Yu
Y
Adachi
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
Taishi
T
Onodera
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
Yuki
Y
Yamada
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
Rina
R
Daio
Department of Microbiology, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Shinagawa-ku, Tokyo 142-8501, Japan.
Makoto
M
Tsuiji
Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan.
Takeshi
T
Inoue
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
Kazuo
K
Kobayashi
Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
Tomohiro
T
Kurosaki
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan.
Manabu
M
Ato
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo 162-8640, Japan ytakahas@niid.go.jp.
Yoshimasa
Y
Takahashi
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology; D003429:Cross Reactions; D018858:Germinal Center / Q000276:immunology*; D007074:Immunoglobulin G / Q000276:immunology; D007156:Immunologic Memory; D009980:Influenza A virus / Q000472:pathogenicity; D008168:Lung / Q000276:immunology / Q000821:virology; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009154:Mutation; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D061905:Single-Domain Antibodies / Q000235:genetics / Q000276:immunology
D007074:Immunoglobulin G; D061905:Single-Domain Antibodies