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

English version

Autoři: Jessica K. Fiege ^aff001; Ian A. Stone ^aff001; Rebekah E. Dumm ^aff002; Barbara M. Waring ^aff001; Brian T. Fife ^aff003; Judith Agudo ^aff004; Brian D. Brown ^aff004; Nicholas S. Heaton ^aff002; Ryan A. Langlois ^aff001
Působiště autorů: University of Minnesota, Department of Microbiology and Immunology and the Center for Immunology, Minneapolis, Minnesota, United States of America ^aff001; Duke University School of Medicine, Department of Molecular Genetics and Microbiology, Durham, North Carolina, United States of America ^aff002; University of Minnesota, Department of Medicine and the Center for Immunology, Minneapolis, Minnesota, United States of America ^aff003; Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, New York City, New York, United States of America ^aff004
Vyšlo v časopise: Long-term surviving influenza infected cells evade CD8+ T cell mediated clearance. PLoS Pathog 15(9): e32767. doi:10.1371/journal.ppat.1008077
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1008077

Souhrn

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.

Klíčová slova:

Cell cycle and cell division – Cell staining – Cytotoxic T cells – Epithelial cells – Flow cytometry – Influenza A virus – T cells

Zdroje

1. Fiege JK, Langlois RA. Investigating influenza A virus infection: tools to track infection and limit tropism. Journal of virology. 2015;89(12):6167–70. doi: 10.1128/JVI.00462-15 25855737; PubMed Central PMCID: PMC4474293.

2. Heaton NS, Langlois RA, Sachs D, Lim JK, Palese P, tenOever BR. Long-term survival of influenza virus infected club cells drives immunopathology. The Journal of experimental medicine. 2014;211(9):1707–14. doi: 10.1084/jem.20140488 25135297; PubMed Central PMCID: PMC4144728.

3. Reuther P, Gopfert K, Dudek AH, Heiner M, Herold S, Schwemmle M. Generation of a variety of stable Influenza A reporter viruses by genetic engineering of the NS gene segment. Sci Rep. 2015;5:11346. doi: 10.1038/srep11346 26068081; PubMed Central PMCID: PMC4464305.

4. Hamilton JR, Sachs D, Lim JK, Langlois RA, Palese P, Heaton NS. Club cells surviving influenza A virus infection induce temporary nonspecific antiviral immunity. Proceedings of the National Academy of Sciences of the United States of America. 2016;113(14):3861–6. doi: 10.1073/pnas.1522376113 27001854; PubMed Central PMCID: PMC4833272.

5. Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell. 2014;15(2):123–38. doi: 10.1016/j.stem.2014.07.012 25105578; PubMed Central PMCID: PMC4212493.

6. Vaughan AE, Brumwell AN, Xi Y, Gotts JE, Brownfield DG, Treutlein B, et al. Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature. 2015;517(7536):621–5. doi: 10.1038/nature14112 25533958; PubMed Central PMCID: PMC4312207.

7. Zuo W, Zhang T, Wu DZ, Guan SP, Liew AA, Yamamoto Y, et al. p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature. 2015;517(7536):616–20. doi: 10.1038/nature13903 25383540.

8. Ray S, Chiba N, Yao C, Guan X, McConnell AM, Brockway B, et al. Rare SOX2(+) Airway Progenitor Cells Generate KRT5(+) Cells that Repopulate Damaged Alveolar Parenchyma following Influenza Virus Infection. Stem Cell Reports. 2016;7(5):817–25. doi: 10.1016/j.stemcr.2016.09.010 27773701; PubMed Central PMCID: PMC5106521.

9. Quantius J, Schmoldt C, Vazquez-Armendariz AI, Becker C, El Agha E, Wilhelm J, et al. Influenza Virus Infects Epithelial Stem/Progenitor Cells of the Distal Lung: Impact on Fgfr2b-Driven Epithelial Repair. PLoS pathogens. 2016;12(6):e1005544. doi: 10.1371/journal.ppat.1005544 27322618; PubMed Central PMCID: PMC4913929.

10. Topham DJ, Tripp RA, Doherty PC. CD8+ T cells clear influenza virus by perforin or Fas-dependent processes. J Immunol. 1997;159(11):5197–200. 9548456.

11. Hufford MM, Kim TS, Sun J, Braciale TJ. Antiviral CD8+ T cell effector activities in situ are regulated by target cell type. The Journal of experimental medicine. 2011;208(1):167–80. doi: 10.1084/jem.20101850 21187318; PubMed Central PMCID: PMC3023137.

12. Brincks EL, Katewa A, Kucaba TA, Griffith TS, Legge KL. CD8 T cells utilize TRAIL to control influenza virus infection. J Immunol. 2008;181(7):4918–25. doi: 10.4049/jimmunol.181.7.4918 18802095; PubMed Central PMCID: PMC2610351.

13. Agudo J, Park ES, Rose SA, Alibo E, Sweeney R, Dhainaut M, et al. Quiescent Tissue Stem Cells Evade Immune Surveillance. Immunity. 2018;48(2):271–85 e5. doi: 10.1016/j.immuni.2018.02.001 29466757; PubMed Central PMCID: PMC5824652.

14. Petersen JL, Morris CR, Solheim JC. Virus evasion of MHC class I molecule presentation. J Immunol. 2003;171(9):4473–8. doi: 10.4049/jimmunol.171.9.4473 14568919.

15. Rutigliano JA, Sharma S, Morris MY, Oguin TH, 3rd, McClaren JL, Doherty PC, et al. Highly pathological influenza A virus infection is associated with augmented expression of PD-1 by functionally compromised virus-specific CD8+ T cells. Journal of virology. 2014;88(3):1636–51. doi: 10.1128/JVI.02851-13 24257598; PubMed Central PMCID: PMC3911576.

16. McNally B, Ye F, Willette M, Flano E. Local blockade of epithelial PDL-1 in the airways enhances T cell function and viral clearance during influenza virus infection. Journal of virology. 2013;87(23):12916–24. doi: 10.1128/JVI.02423-13 24067957; PubMed Central PMCID: PMC3838157.

17. Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996;4(1):25–36. doi: 10.1016/s1074-7613(00)80295-2 8574849.

18. Guidotti LG, Rochford R, Chung J, Shapiro M, Purcell R, Chisari FV. Viral clearance without destruction of infected cells during acute HBV infection. Science. 1999;284(5415):825–9. doi: 10.1126/science.284.5415.825 10221919.

19. Sjaastad LE, Fay EJ, Fiege JK, Macchietto MG, Stone IA, Markman MW, et al. Distinct antiviral signatures revealed by the magnitude and round of influenza virus replication in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2018;115(38):9610–5. doi: 10.1073/pnas.1807516115 30181264; PubMed Central PMCID: PMC6156629.

20. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. doi: 10.1146/annurev.immunol.26.021607.090331 18173375.

21. Agudo J, Ruzo A, Park ES, Sweeney R, Kana V, Wu M, et al. GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions. Nature biotechnology. 2015;33(12):1287–92. doi: 10.1038/nbt.3386 26524661; PubMed Central PMCID: PMC4675673.

22. Muzumdar MD, Tasic B, Miyamichi K, Li L, Luo L. A global double-fluorescent Cre reporter mouse. Genesis. 2007;45(9):593–605. doi: 10.1002/dvg.20335 17868096.

23. Mehta S, Jeffrey KL. Beyond receptors and signaling: epigenetic factors in the regulation of innate immunity. Immunol Cell Biol. 2015;93(3):233–44. doi: 10.1038/icb.2014.101 25559622; PubMed Central PMCID: PMC4885213.

24. Chambers BS, Heaton BE, Rausch K, Dumm RE, Hamilton JR, Cherry S, et al. DNA mismatch repair is required for the host innate response and controls cellular fate after influenza virus infection. Nat Microbiol. 2019. doi: 10.1038/s41564-019-0509-3 31358986.

25. Jiang W, Wang Q, Chen S, Gao S, Song L, Liu P, et al. Influenza A virus NS1 induces G0/G1 cell cycle arrest by inhibiting the expression and activity of RhoA protein. Journal of virology. 2013;87(6):3039–52. doi: 10.1128/JVI.03176-12 23283961; PubMed Central PMCID: PMC3592114.

26. Shoemaker JE, Fukuyama S, Eisfeld AJ, Muramoto Y, Watanabe S, Watanabe T, et al. Integrated network analysis reveals a novel role for the cell cycle in 2009 pandemic influenza virus-induced inflammation in macaque lungs. BMC Syst Biol. 2012;6:117. doi: 10.1186/1752-0509-6-117 22937776; PubMed Central PMCID: PMC3481363.

27. Zhu L, Zhao W, Lu J, Li S, Zhou K, Jiang W, et al. Influenza virus matrix protein M1 interacts with SLD5 to block host cell cycle. Cell Microbiol. 2019;21(8):e13038. doi: 10.1111/cmi.13038 31050118.

28. Duan S, Thomas PG. Balancing Immune Protection and Immune Pathology by CD8(+) T-Cell Responses to Influenza Infection. Front Immunol. 2016;7:25. doi: 10.3389/fimmu.2016.00025 26904022; PubMed Central PMCID: PMC4742794.

29. Newton AH, Cardani A, Braciale TJ. The host immune response in respiratory virus infection: balancing virus clearance and immunopathology. Semin Immunopathol. 2016;38(4):471–82. doi: 10.1007/s00281-016-0558-0 26965109; PubMed Central PMCID: PMC4896975.

30. Guidotti LG, Borrow P, Brown A, McClary H, Koch R, Chisari FV. Noncytopathic clearance of lymphocytic choriomeningitis virus from the hepatocyte. The Journal of experimental medicine. 1999;189(10):1555–64. doi: 10.1084/jem.189.10.1555 10330434; PubMed Central PMCID: PMC2193644.

31. Burdeinick-Kerr R, Griffin DE. Gamma interferon-dependent, noncytolytic clearance of sindbis virus infection from neurons in vitro. Journal of virology. 2005;79(9):5374–85. doi: 10.1128/JVI.79.9.5374-5385.2005 15827152; PubMed Central PMCID: PMC1082728.

32. Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, Lawson B, et al. CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS pathogens. 2010;6(1):e1000747. doi: 10.1371/journal.ppat.1000747 20126441; PubMed Central PMCID: PMC2813271.

33. Wong JK, Strain MC, Porrata R, Reay E, Sankaran-Walters S, Ignacio CC, et al. In vivo CD8+ T-cell suppression of siv viremia is not mediated by CTL clearance of productively infected cells. PLoS pathogens. 2010;6(1):e1000748. doi: 10.1371/journal.ppat.1000748 20126442; PubMed Central PMCID: PMC2813272.

34. Erickson JJ, Gilchuk P, Hastings AK, Tollefson SJ, Johnson M, Downing MB, et al. Viral acute lower respiratory infections impair CD8+ T cells through PD-1. J Clin Invest. 2012;122(8):2967–82. doi: 10.1172/JCI62860 22797302; PubMed Central PMCID: PMC3408742.

35. Erickson JJ, Rogers MC, Tollefson SJ, Boyd KL, Williams JV. Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection. J Immunol. 2016;197(1):233–43. doi: 10.4049/jimmunol.1502115 27259857; PubMed Central PMCID: PMC4933524.

36. Attanasio J, Wherry EJ. Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity. 2016;44(5):1052–68. doi: 10.1016/j.immuni.2016.04.022 27192569; PubMed Central PMCID: PMC4873956.

37. Pauken KE, Nelson CE, Martinov T, Spanier JA, Heffernan JR, Sahli NL, et al. Cutting edge: identification of autoreactive CD4+ and CD8+ T cell subsets resistant to PD-1 pathway blockade. J Immunol. 2015;194(8):3551–5. doi: 10.4049/jimmunol.1402262 25769925; PubMed Central PMCID: PMC4390507.

38. Fay EJ, Aron SL, Stone IA, Waring BM, Plemper RK, Langlois RA. Engineered Small-Molecule Control of Influenza A Virus Replication. Journal of virology. 2019;93(1). doi: 10.1128/JVI.01677-18 30282710; PubMed Central PMCID: PMC6288343.

39. Heaton NS, Sachs D, Chen CJ, Hai R, Palese P. Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins. Proceedings of the National Academy of Sciences of the United States of America. 2013;110(50):20248–53. doi: 10.1073/pnas.1320524110 24277853; PubMed Central PMCID: PMC3864309.

40. Fiege JK, Stone IA, Fay EJ, Markman MW, Wijeyesinghe S, Macchietto MG, et al. The Impact of TCR Signal Strength on Resident Memory T Cell Formation during Influenza Virus Infection. J Immunol. 2019. doi: 10.4049/jimmunol.1900093 31235552.

41. Langlois RA, Varble A, Chua MA, Garcia-Sastre A, tenOever BR. Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(30):12117–22. doi: 10.1073/pnas.1206039109 22778433; PubMed Central PMCID: PMC3409765.