B cell deficiency induces cytotoxic memory CD8<sup>+</sup> T cells during influenza-associated bacterial pneumonia

Leigh M. Miller; Alexis M. Duray; Ellyse M. Cipolla; Flavia Rago; Brooke P. Dresden; Kristen L. Parenteau; Abhigya Gupta; John F. Alcorn

doi:10.1172/JCI188342

¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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¹Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, United States of America

²Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, United States of America

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J Clin Invest. https://doi.org/10.1172/JCI188342.
Copyright © 2025, Miller et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 10, 2025 - Version history

Influenza-associated bacterial super-infections in the lung lead to increased morbidity and mortality. Nearly all people have pre-existing memory to influenza virus, which can protect against subsequent infection in the lung. This study explored the role B cells play in protection against bacterial (Staphylococcus aureus or Klebsiella pneumoniae) super-infection with previous heterotypic influenza memory. B cell deficiency resulted in an increased inflammatory lung environment and lung tissue injury during super-infection. Loss of B cells increased populations of memory CD8⁺ T cells in the lung and these CD8⁺ T cells were transcriptionally and functionally distinct from WT mice. Use of antibody-deficient mouse models showed that this phenotype was specifically due to loss of antibody production from B cells. Passive immunization with influenza-antibody serum in B cell deficient mice rescued the CD8⁺ T cell phenotype. CD8⁺ T cell depletion and lethal super-infection challenge experiments showed that the cytotoxic memory CD8⁺ T cells from B cell deficient mice protect against super-infection bacterial burden and mortality. These findings provide insight into the importance of B cells for regulating immune responses against infection.

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B cell deficiency induces cytotoxic memory CD8⁺ T cells during influenza-associated bacterial pneumonia

Leigh M. Miller,¹ Alexis M. Duray,¹ Ellyse M. Cipolla,¹ Flavia Rago,¹ Brooke P. Dresden,¹ Kristen L. Parenteau,¹ Abhigya Gupta,² and John F. Alcorn¹

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B cell deficiency induces cytotoxic memory CD8+ T cells during influenza-associated bacterial pneumonia

Leigh M. Miller,1 Alexis M. Duray,1 Ellyse M. Cipolla,1 Flavia Rago,1 Brooke P. Dresden,1 Kristen L. Parenteau,1 Abhigya Gupta,2 and John F. Alcorn1

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B cell deficiency induces cytotoxic memory CD8⁺ T cells during influenza-associated bacterial pneumonia

Leigh M. Miller,¹ Alexis M. Duray,¹ Ellyse M. Cipolla,¹ Flavia Rago,¹ Brooke P. Dresden,¹ Kristen L. Parenteau,¹ Abhigya Gupta,² and John F. Alcorn¹