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Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles
Angela Pizzolla, … , Katherine Kedzierska, Linda M. Wakim
Angela Pizzolla, … , Katherine Kedzierska, Linda M. Wakim
Published January 8, 2018
Citation Information: J Clin Invest. 2018;128(2):721-733. https://doi.org/10.1172/JCI96957.
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Research Article Immunology Infectious disease

Influenza-specific lung-resident memory T cells are proliferative and polyfunctional and maintain diverse TCR profiles

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Abstract

The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung CD8+ Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific CD8+ Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of CD8+ Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus–specific CD8+ T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific CD8+ T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza–specific CD8+ Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other CD8+ T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants.

Authors

Angela Pizzolla, Thi H.O. Nguyen, Sneha Sant, Jade Jaffar, Tom Loudovaris, Stuart I. Mannering, Paul G. Thomas, Glen P. Westall, Katherine Kedzierska, Linda M. Wakim

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Figure 1

Location and phenotype of resident memory T cells in healthy human lung.

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Location and phenotype of resident memory T cells in healthy human lung....
(A) Microscopy of human lung tissue with CD3 (yellow) and DAPI staining. Scale bars: 1000mm. (B) Flow cytometry profiles depicting the level of expression of CD103 and CD69 on memory CD8+ (CD45RO+CD8+CD3+) T cells isolated from human lung. (C) Flow cytometry profiles depicting the level of expression of CD103 and CD69 on memory CD8+, CD4+, and CD4–CD8– (CD45RO+CD3+) T cells isolated from human lung. (D) The percentages of antigen-experienced (CD3+CD45RO+) CD8+ T cells in human lung tissue that express CD103+ and CD69+. Dots represent individual donors (n = 10 healthy lungs), and bars depict mean ± SEM (1-way ANOVA, Tukey’s multiple comparison). (E) The percentage of CD8+ Trm cells (CD8+CD45RO+CD103+CD69+) of the total antigen-experienced CD8+ T cell pool (CD3+CD8+CD45RO+) in the lungs of donors plotted against age (years). Dots represent individual donors. (F) The percentage of antigen-experienced (CD3+CD45RO+) CD8– T cells in human lung tissue that express CD103+ and CD69+. Dots represent individual donors (n = 10 healthy lung tissues), and bars depict mean ± SEM (1-way ANOVA, Tukey’s multiple comparison). (G) The proportion of antigen-experienced CD8+ T cells (CD3+CD45RO+CD8+) isolated from the lung, blood, or spleen of donors that express CD103 and CD69. Bars represent individual donors. (H and I) Representative histograms depicting the level of expression of CD28 on CD103+CD69+, CD103–CD69–, and CD103–CD69+ subsets of antigen-experienced CD8+ T cells (CD3+CD8+CD45RO+) isolated from the (H) lung and (I) spleen of healthy donors. (J and K) Graphs depict the mean fluorescence intensity (MFI) of CD28 on subsets of antigen-experienced CD8+ T cells isolated from the (J) lung and (K) spleen. Symbols represent individual donors (1-way ANOVA, Tukey’s multiple comparison). *P < 0.05; ****P < 0.0001.

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