tetano
Editor, Senior Moderator
Cell Rep
. 2024 Nov 22;43(12):114990.
doi: 10.1016/j.celrep.2024.114990. Online ahead of print. Modulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem
Sila Ataca[SUP] 1 [/SUP], Maya Sangesland[SUP] 2 [/SUP], Rebeca de Paiva Fróes Rocha[SUP] 3 [/SUP], Alba Torrents de la Peña[SUP] 3 [/SUP], Larance Ronsard[SUP] 2 [/SUP], Seyhan Boyoglu-Barnum[SUP] 1 [/SUP], Rebecca A Gillespie[SUP] 1 [/SUP], Yaroslav Tsybovsky[SUP] 4 [/SUP], Tyler Stephens[SUP] 4 [/SUP], Syed M Moin[SUP] 1 [/SUP], Julia Lederhofer[SUP] 1 [/SUP], Adrian Creanga[SUP] 1 [/SUP], Sarah F Andrews[SUP] 1 [/SUP], Ralston M Barnes[SUP] 5 [/SUP], Daniel Rohrer[SUP] 5 [/SUP], Nils Lonberg[SUP] 5 [/SUP], Barney S Graham[SUP] 1 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Daniel Lingwood[SUP] 2 [/SUP], Masaru Kanekiyo[SUP] 6 [/SUP]
Affiliations
Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-69[SUP]∗[/SUP]01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses.
Keywords: B cell; CP: Immunology; HA stem; IGHD3-9; IGHV1-69; bnAb; broadly neutralizing antibody; germline-targeting; hemagglutinin; influenza virus; nanoparticle.
. 2024 Nov 22;43(12):114990.
doi: 10.1016/j.celrep.2024.114990. Online ahead of print. Modulating the immunodominance hierarchy of immunoglobulin germline-encoded structural motifs targeting the influenza hemagglutinin stem
Sila Ataca[SUP] 1 [/SUP], Maya Sangesland[SUP] 2 [/SUP], Rebeca de Paiva Fróes Rocha[SUP] 3 [/SUP], Alba Torrents de la Peña[SUP] 3 [/SUP], Larance Ronsard[SUP] 2 [/SUP], Seyhan Boyoglu-Barnum[SUP] 1 [/SUP], Rebecca A Gillespie[SUP] 1 [/SUP], Yaroslav Tsybovsky[SUP] 4 [/SUP], Tyler Stephens[SUP] 4 [/SUP], Syed M Moin[SUP] 1 [/SUP], Julia Lederhofer[SUP] 1 [/SUP], Adrian Creanga[SUP] 1 [/SUP], Sarah F Andrews[SUP] 1 [/SUP], Ralston M Barnes[SUP] 5 [/SUP], Daniel Rohrer[SUP] 5 [/SUP], Nils Lonberg[SUP] 5 [/SUP], Barney S Graham[SUP] 1 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Daniel Lingwood[SUP] 2 [/SUP], Masaru Kanekiyo[SUP] 6 [/SUP]
Affiliations
- PMID: 39580804
- DOI: 10.1016/j.celrep.2024.114990
Antibodies targeting epitopes through germline-encoded motifs can be found in different individuals. While these public antibodies are often beneficial, they also pose hurdles for subdominant antibodies to emerge. Here, we use transgenic mice that reproduce the human IGHV1-69[SUP]∗[/SUP]01 germline-encoded antibody response to the conserved stem epitope on group 1 hemagglutinin (HA) of influenza A virus to show that this germline-endowed response can be overridden by a subdominant yet cross-group reactive public antibody response. Immunization with a non-cognate group 2 HA stem enriched B cells harboring the IGHD3-9 gene, thereby switching from IGHV1-69- to IGHD3-9-encoded motif-dependent epitope recognition. These IGHD3-9 antibodies bound, neutralized, and conferred cross-group protection in mice against influenza A viruses. A cryoelectron microscopy (cryo-EM) structure of an IGHD3-9 antibody resembled the human broadly neutralizing antibody FI6v3, which uses IGHD3-9. Together, our findings offer insights into vaccine regimens that engage an immunoglobulin repertoire with broader cross-reactivity to influenza A viruses.
Keywords: B cell; CP: Immunology; HA stem; IGHD3-9; IGHV1-69; bnAb; broadly neutralizing antibody; germline-targeting; hemagglutinin; influenza virus; nanoparticle.