B cell deficiency induces cytotoxic memory CD8+ 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
Leigh M. Miller, Alexis M. Duray, Ellyse M. Cipolla, Flavia Rago, Brooke P. Dresden, Kristen L. Parenteau, Abhigya Gupta, John F. Alcorn
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Research Article Immunology Infectious disease

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

Abstract

Influenza-associated bacterial superinfections in the lung lead to increased morbidity and mortality. Nearly all people have preexisting 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) superinfection with previous heterotypic influenza memory. B cell deficiency resulted in an increased inflammatory lung environment and lung tissue injury during superinfection. 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 those of 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 superinfection challenge experiments showed that the cytotoxic memory CD8+ T cells from B cell–deficient mice protect against superinfection bacterial burden and mortality. These findings provide insight into the importance of B cells for regulating immune responses against infection.

Authors

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

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Figure 8

CD8+ T cells induced by B cell deficiency promote bacterial control during memory superinfection.

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CD8+ T cells induced by B cell deficiency promote bacterial control duri...
(A) CD8+ T cell depletion scheme. IT, intratracheal. (B) CD8β T cell depletion was confirmed on day of tissue harvesting via flow cytometry (μMT–CD8β-depleted: n = 8; WT–CD8β-depleted: n = 8; μMT-ISO: n = 8; WT-ISO: n = 8). (C) MRSA burden in lung homogenates (μMT–CD8β-depleted: n = 8; WT–CD8β-depleted: n = 8; μMT-ISO: n = 7; WT-ISO: n = 7). (D) Viral protein (PR8) was assessed via quantitative PCR (μMT–CD8β-depleted: n = 8; WT–CD8β-depleted: n = 8; μMT-ISO: n = 8; WT-ISO: n = 8). (E) BALF granzyme B protein concentration (μMT–CD8β-depleted: n = 8; WT–CD8β-depleted: n = 8; μMT-ISO: n = 8; WT-ISO: n = 8). (F) WT and μMT mice were challenged with a lethal dose of MRSA (2 × 108) during memory superinfection and weighed daily (left). PR8-induced weight loss prior to MRSA challenge (day 54 to day 60) (right), and percentage of weight loss 48 hours following MRSA challenge (day 62) (middle) (WT: n = 22; μMT: n = 21). (G) Left: Survival percentage was calculated daily after lethal MRSA challenge. Right: Median day of mortality was calculated for WT and μMT groups (WT: n = 22; μMT: n = 21). (H) MRSA burden 14 hours after lethal MRSA challenge in lung homogenate (WT: n = 14; μMT: n = 13). Data are represented as mean ± SEM. For B–E, P values were determined by repeated 1-way ANOVA measures; for F–H, P values were determined by repeated 2-tailed Mann-Whitney U test (*P < 0.05, **P < 0.01, ***P <0.001, ****P < 0.0001).