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

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 2

Functional profiles of memory CD8+ T cells in human lung tissue.

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Functional profiles of memory CD8+ T cells in human lung tissue. Proport...
Proportion of antigen-experienced CD8+ T cells isolated from lung tissue expressing (A) TNF-α or (B) IFN-γ at various time points after stimulation with PMA/ION. Seven donors are shown. (C) CD103 and CD69 expression by CD8+CD45RO+ T cells delineates 3 subsets: CD103+CD69+ (Trm), CD103–CD69+, and CD103–CD69–. (D and E) Representative flow cytometry profiles showing the proportion of CD107a+ cells for each subset following 4 hours of stimulation with PMA/ION. Red dots indicate stimulated samples, while contour plots show unstimulated control cells. (E) Graph depicts data pooled from 4 donors; dots represent individual donors and bars represent mean ± SEM (n = 4, 1-way ANOVA, Tukey’s multiple comparison). (F–J) T cells isolated from human lung were stimulated for 5 hours with PMA/ION and the proportion of each CD8+ T cell subset (delineated as described in C) synthesizing (F) perforin, (G) granzyme B, (H) TNF-α, (I) IFN-γ, and (J) IL-2 was assessed by intracellular cytokine staining. Dots represent individual donors, and bars represent mean ± SEM (n = 4–7, 1-way ANOVA, Tukey’s multiple comparison). (K) Polyfunctional profiles of antigen-experienced CD8+ T cell subsets. Pie charts corresponding to polyfunctional profiles of CD103+CD69+ (Trm), CD103–CD69+, and CD103–CD69– T cell subsets isolated from human lung tissue (n = 7) following 5 hours of stimulation with PMA/ION. Assessment of the mean proportion of cells making any combination of 1–4 cytokines (IFN-γ, TNF, IL-2, and granzyme B). (L) Dots depict individual donors, with bars representing mean + SEM. *P < 0.05; **P < 0.01; ***P < 0.001.