Long-term surviving influenza infected cells evade CD8+ T cell mediated clearance

Jessica K. Fiege, Ian A. Stone, Rebekah E. Dumm, Barbara M. Waring, Brian T. Fife, Judith Agudo, Brian D. Brown, Nicholas S. Heaton, Ryan A. Langlois

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Influenza A virus (IAV) is a seasonal pathogen with the potential to cause devastating pandemics. IAV infects multiple epithelial cell subsets in the respiratory tract, eliciting damage to the lungs. Clearance of IAV is primarily dependent on CD8+ T cells, which must balance control of the infection with immunopathology. Using a virus expressing Cre recombinase to permanently label infected cells in a Cre-inducible reporter mouse, we previously discovered infected club cells that survive both lytic virus replication and CD8+ T cell-mediated clearance. In this study, we demonstrate that ciliated epithelial cells, type I and type II alveolar cells can also become survivor cells. Survivor cells are stable in the lung long-term and demonstrate enhanced proliferation compared to uninfected cells. When we investigated how survivor cells evade CD8+ T cell killing we observed that survivor cells upregulated the inhibitory ligand PD-L1, but survivor cells did not use PD-L1 to evade CD8+ T cell killing. Instead our data suggest that survivor cells are not inherently resistant to CD8+ T cell killing, but instead no longer present IAV antigen and cannot be detected by CD8+ T cells. Finally, we evaluate the failure of CD8+ T cells to kill these previously infected cells. This work demonstrates that additional cell types can survive IAV infection and that these cells robustly proliferate and are stable long term. By sparing previously infected cells, the adaptive immune system may be minimizing pathology associated with IAV infection.

Original languageEnglish (US)
Article numbere1008077
JournalPLoS pathogens
Volume15
Issue number9
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was supported by NIH K22 AI110581 and NIH R01 AI132962 to RAL. JKF was supported by T32 HL007741. RED is supported by the NIH Training grant T32-GM007184-41. NSH is partially supported by 1R21-AI133444 and 1R01- HL142985.*%blankline%*

Publisher Copyright:
Copyright © 2019 Fiege et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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