Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling

Masato Ogishi¹, Koji Kitaoka², Kim L Good-Jacobson³, Darawan Rinchai⁴, Baihao Zhang⁵, Jun Wang², Vincent Gies⁶, Geetha Rao⁷, Tina Nguyen⁸, Danielle T Avery⁷, Taushif Khan⁹, Megan E Smithmyer¹⁰, Joseph Mackie⁸, Rui Yang⁴, Andrés Augusto Arias¹¹, Takaki Asano⁴, Khoren Ponsin⁴, Matthieu Chaldebas⁴, Peng Zhang⁴, Jessica N Peel⁴, Jonathan Bohlen¹², Romain Lévy¹², Simon J Pelham⁴, Wei-Te Lei⁴, Ji Eun Han⁴, Iris Fagniez⁴, Maya Chrabieh¹², Candice Laine¹², David Langlais¹³, Conor Gruber¹⁴, Fatima Al Ali⁹, Mahbuba Rahman⁹, Caner Aytekin¹⁵, Basilin Benson¹⁶, Matthew J Dufort¹⁶, Clara Domingo-Vila¹⁷, Kunihiko Moriya¹⁸, Mark Shlomchik¹⁹, Gulbu Uzel²⁰, Paul E Gray²¹, Daniel Suan²², Kahn Preece²³, Ignatius Chua²⁴, Satoshi Okada²⁵, Shunsuke Chikuma²⁶, Hiroshi Kiyonari²⁷, Timothy I Tree¹⁷, Dusan Bogunovic¹⁴, Philippe Gros²⁸, Nico Marr²⁹, Cate Speake³⁰, Richard A Oram³¹, Vivien Béziat¹², Jacinta Bustamante³², Laurent Abel³³, Bertrand Boisson³³, Anne-Sophie Korganow⁶, Cindy S Ma³⁴, Matthew B Johnson³¹, Kenji Chamoto³⁵, Stéphanie Boisson-Dupuis³³, Tasuku Honjo², Jean-Laurent Casanova³⁶, Stuart G Tangye³⁷

Affiliations

¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; The David Rockefeller Graduate Program, Rockefeller University, New York, NY 10065, USA. Electronic address: oogishi-tky@umin.ac.jp.
² Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan.
³ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁴ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
⁵ Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan; Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
⁶ Department of Clinical Immunology and Internal Medicine, Strasbourg University Hospital, INSERM UMR-S1109, 67000 Strasbourg, France.
⁷ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
⁸ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia.
⁹ Department of Human Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
¹⁰ Center for Interventional Immunology, Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA 98101, USA.
¹¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia; School of Microbiology, University of Antioquia UdeA, Medellin, Colombia.
¹² Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France.
¹³ McGill University Genome Center, Montreal, QC, Canada; McGill Research Centre on Complex Traits, Dahdaleh Institute of Genomic Medicine, Montreal, QC H3A 0G1, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
¹⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁵ Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
¹⁶ Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA.
¹⁷ Department of Immunobiology, School of Immunobiology & Microbial Sciences, Kings' College London, London WC2R 2LS, UK.
¹⁸ Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan.
¹⁹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
²⁰ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
²¹ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia.
²² Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia; Westmead Clinical School, The University of Sydney, Westmead, NSW 2145, Australia.
²³ John Hunter Children's Hospital, Newcastle, NSW 2305, Australia.
²⁴ Canterbury Health Laboratories, Christchurch 8140, New Zealand.
²⁵ Department of Pediatrics, Hiroshima University Hospital, Hiroshima 734-0037, Japan.
²⁶ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-0016, Japan.
²⁷ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
²⁸ McGill Research Centre on Complex Traits, Dahdaleh Institute of Genomic Medicine, Montreal, QC H3A 0G1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 0G1, Canada.
²⁹ Department of Human Immunology, Research Branch, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
³⁰ Center for Interventional Immunology, Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA 98101, USA; Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA 98101, USA.
³¹ Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2ED, UK.
³² St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France; Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
³³ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France.
³⁴ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia.
³⁵ Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan; Department of Immuno-Oncology PDT, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan.
³⁶ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France; Department of Pediatrics, Necker Hospital for Sick Children, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA.
³⁷ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia. Electronic address: s.tangye@garvan.org.au.

PMID: 39603236
PMCID: PMC11634639 (available on 2025-12-10)
DOI: 10.1016/j.immuni.2024.10.014

Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling

Masato Ogishi et al. Immunity. 2024.

. 2024 Dec 10;57(12):2790-2807.e15.

doi: 10.1016/j.immuni.2024.10.014. Epub 2024 Nov 26.

Authors

Affiliations

¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; The David Rockefeller Graduate Program, Rockefeller University, New York, NY 10065, USA. Electronic address: oogishi-tky@umin.ac.jp.
² Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan.
³ Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
⁴ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
⁵ Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan; Laboratory for Mucosal Immunity, Center for Integrative Medical Sciences, RIKEN Yokohama Institute, Yokohama 230-0045, Japan.
⁶ Department of Clinical Immunology and Internal Medicine, Strasbourg University Hospital, INSERM UMR-S1109, 67000 Strasbourg, France.
⁷ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
⁸ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia.
⁹ Department of Human Immunology, Research Branch, Sidra Medicine, Doha, Qatar.
¹⁰ Center for Interventional Immunology, Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA 98101, USA.
¹¹ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Primary Immunodeficiencies Group, University of Antioquia UdeA, Medellin, Colombia; School of Microbiology, University of Antioquia UdeA, Medellin, Colombia.
¹² Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France.
¹³ McGill University Genome Center, Montreal, QC, Canada; McGill Research Centre on Complex Traits, Dahdaleh Institute of Genomic Medicine, Montreal, QC H3A 0G1, Canada; Department of Human Genetics, McGill University, Montreal, QC H3A 0G1, Canada.
¹⁴ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
¹⁵ Department of Pediatric Immunology, Dr. Sami Ulus Maternity and Children's Health and Diseases Training and Research Hospital, Ankara, Turkey.
¹⁶ Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA.
¹⁷ Department of Immunobiology, School of Immunobiology & Microbial Sciences, Kings' College London, London WC2R 2LS, UK.
¹⁸ Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai 980-0872, Japan.
¹⁹ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
²⁰ Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
²¹ Department of Immunology and Infectious Diseases, Sydney Children's Hospital, High Street, Randwick, NSW 2031, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW 2052, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia.
²² Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia; Westmead Clinical School, The University of Sydney, Westmead, NSW 2145, Australia.
²³ John Hunter Children's Hospital, Newcastle, NSW 2305, Australia.
²⁴ Canterbury Health Laboratories, Christchurch 8140, New Zealand.
²⁵ Department of Pediatrics, Hiroshima University Hospital, Hiroshima 734-0037, Japan.
²⁶ Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-0016, Japan.
²⁷ Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo 650-0047, Japan.
²⁸ McGill Research Centre on Complex Traits, Dahdaleh Institute of Genomic Medicine, Montreal, QC H3A 0G1, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 0G1, Canada.
²⁹ Department of Human Immunology, Research Branch, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
³⁰ Center for Interventional Immunology, Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA 98101, USA; Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA 98101, USA.
³¹ Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter EX1 2ED, UK.
³² St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France; Center for the Study of Primary Immunodeficiencies, Necker Hospital for Sick Children Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
³³ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France.
³⁴ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia.
³⁵ Department of Immunology and Genomic Medicine, Center for Cancer Immunotherapy and Immunobiology, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan; Department of Immuno-Oncology PDT, Kyoto University Graduate School of Medicine, Kyoto 606-8303, Japan.
³⁶ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France; Paris Cité University, Imagine Institute, Paris, France; Department of Pediatrics, Necker Hospital for Sick Children, 75015 Paris, France; Howard Hughes Medical Institute, New York, NY 10065, USA.
³⁷ Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW 2052, Australia; Clinical Immunogenomics Research Consortium Australasia (CIRCA), Darlinghurst, NSW 2010, Australia. Electronic address: s.tangye@garvan.org.au.

PMID: 39603236
PMCID: PMC11634639 (available on 2025-12-10)
DOI: 10.1016/j.immuni.2024.10.014

Abstract

T follicular helper (Tfh) cells abundantly express the immunoreceptor programmed cell death protein 1 (PD-1), and the impact of PD-1 deficiency on antibody (Ab)-mediated immunity in mice is associated with compromised Tfh cell functions. Here, we revisited the role of the PD-1-PD-L1 axis on Ab-mediated immunity. Individuals with inherited PD-1 or PD-L1 deficiency had fewer memory B cells and impaired Ab responses, similar to Pdcd1^-/- and Cd274^-/-Pdcd1lg2^-/- mice. PD-1, PD-L1, or both could be detected on the surface of human naive B cells following in vitro activation. PD-1- or PD-L1-deficient B cells had reduced expression of the transcriptional regulator c-Myc and c-Myc-target genes in vivo, and PD-1 deficiency or neutralization of PD-1 or PD-L1 impeded c-Myc expression and Ab production in human B cells isolated in vitro. Furthermore, B cell-specific deletion of Pdcd1 prevented the physiological accumulation of memory B cells in mice. Thus, PD-1 shapes optimal B cell memory and Ab-mediated immunity through B cell-intrinsic and B cell-extrinsic mechanisms, suggesting that B cell dysregulation contributes to infectious and autoimmune complications following anti-PD-1-PD-L1 immunotherapy.

Keywords: IL-21; PD-1; PD-L1; T follicular helper cells; antibody; c-Myc; humoral immunity; memory B cells.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

References

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Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling

Affiliations

Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Research Materials