Immunodominance to nonneutralizing epitopes is a roadblock in designing vaccines against several diseases of high interest. One hypothetical possibility is that limited CD4 T cell help to B cells in a normal germinal center (GC) response results in selective recruitment of abundant, immunodominant B cells. This is a central issue in HIV envelope glycoprotein (Env) vaccine designs, because precursors to broadly neutralizing epitopes are rare. Here, we sought to elucidate whether modulating the quantity of T cell help can influence recruitment and competition of broadly neutralizing antibody precursor B cells at a physiological precursor frequency in response to Env trimer immunization. To do so, two new Env-specific CD4 transgenic (Tg) T cell receptor (TCR) mouse lines were generated, carrying TCR pairs derived from Env-protein immunization. Our results suggest that CD4 T cell help quantitatively regulates early recruitment of rare B cells to GCs.
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1 February 2021
Article|
December 23 2020
Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers
Jeong Hyun Lee
,
Jeong Hyun Lee
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
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Joyce K. Hu
,
Joyce K. Hu
Investigation
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
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Erik Georgeson
,
Erik Georgeson
Resources
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
3
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
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Catherine Nakao
,
Catherine Nakao
Formal analysis
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
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Bettina Groschel
,
Bettina Groschel
Resources, Writing - review & editing
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
3
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
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Thamotharampillai Dileepan
,
Thamotharampillai Dileepan
Methodology, Resources
5
Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
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Marc K. Jenkins
,
Marc K. Jenkins
Resources
5
Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
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Gregory Seumois
,
Gregory Seumois
Data curation, Methodology, Resources, Supervision, Validation
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
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Pandurangan Vijayanand
,
Pandurangan Vijayanand
Methodology, Resources
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
6
Clinical and Experimental Sciences, National Institute for Health Research Southampton, Respiratory Biomedical Research Unit, University of Southampton, Southampton, UK
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William R. Schief
,
William R. Schief
Conceptualization, Funding acquisition, Resources, Supervision, Writing - review & editing
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
3
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
7
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA
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Shane Crotty
Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
8
Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA
Correspondence to Shane Crotty: shane@lji.org
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Jeong Hyun Lee
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
Joyce K. Hu
Investigation
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
Erik Georgeson
Resources
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
3
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
Catherine Nakao
Formal analysis
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
Bettina Groschel
Resources, Writing - review & editing
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
3
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
Thamotharampillai Dileepan
Methodology, Resources
5
Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
Marc K. Jenkins
Resources
5
Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN
Gregory Seumois
Data curation, Methodology, Resources, Supervision, Validation
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
Pandurangan Vijayanand
Methodology, Resources
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
6
Clinical and Experimental Sciences, National Institute for Health Research Southampton, Respiratory Biomedical Research Unit, University of Southampton, Southampton, UK
William R. Schief
Conceptualization, Funding acquisition, Resources, Supervision, Writing - review & editing
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
3
International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA
4
Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA
7
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA
Shane Crotty
Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Visualization, Writing - original draft, Writing - review & editing
1
Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA
2
Consortium for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA
8
Department of Medicine, Division of Infectious Diseases and Global Public Health, University of California, San Diego, La Jolla, CA
Disclosures: M.K. Jenkins reported a patent to US2019/044605 issued. W.R. Schief reported grants from Compuvax, Inc outside the submitted work; in addition, W.R. Schief had a patent to BG505 GT3.1 pending and a patent to BG505 MD39 pending. No other disclosures were reported.
Correspondence to Shane Crotty: shane@lji.org
Received:
June 17 2020
Revision Received:
September 23 2020
Accepted:
November 13 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Institutes of Health
(AI100663, AI144462, R01 AI143826, S10 RR027366)
© 2020 Lee et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (2): e20201254.
Article history
Received:
June 17 2020
Revision Received:
September 23 2020
Accepted:
November 13 2020
Citation
Jeong Hyun Lee, Joyce K. Hu, Erik Georgeson, Catherine Nakao, Bettina Groschel, Thamotharampillai Dileepan, Marc K. Jenkins, Gregory Seumois, Pandurangan Vijayanand, William R. Schief, Shane Crotty; Modulating the quantity of HIV Env-specific CD4 T cell help promotes rare B cell responses in germinal centers. J Exp Med 1 February 2021; 218 (2): e20201254. doi: https://doi.org/10.1084/jem.20201254
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