Viral PB1-F2 and host IFN-γ guide ILC2 and T cell activity during influenza virus infection

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 8
• Main Authors: Barman, Tarani Kanta, Huber, Victor C, Bonin, Jesse L, Califano, Danielle, Salmon, Sharon L, McKenzie, Andrew N J, Metzger, Dennis W
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 22-02-2022
• Subjects: Animals; Biological Sciences; CD8 antigen; Disease resistance; Female; Functional plasticity; Immunity, Innate - immunology; Infections; Influenza; Integrity; Interferon; Interferon-gamma - metabolism; Interferons - metabolism; Interleukin 13; Interleukin 5; Interleukin-5 - immunology; Interleukin-5 - metabolism; Lung - metabolism; Lymphocytes; Lymphocytes - immunology; Lymphocytes - metabolism; Lymphocytes T; Lymphoid cells; Male; Mice; Mice, Inbred BALB C; Orthomyxoviridae - metabolism; Orthomyxoviridae - pathogenicity; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - metabolism; Pathogens; Phenotypes; Survival; Swine flu; Viral Proteins - metabolism; Viral Proteins - physiology; Virulence; Virulence - genetics; Virulence factors; Virulence Factors - genetics; Virus Replication - genetics; Viruses; γ-Interferon; influenza; ILCs; IFN-γ; T cells; PB1-F2
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2118535119

Functional plasticity of innate lymphoid cells (ILCs) and T cells is regulated by host environmental cues, but the influence of pathogen-derived virulence factors has not been described. We now report the interplay between host interferon (IFN)-γ and viral PB1-F2 virulence protein in regulating the functions of ILC2s and T cells that lead to recovery from influenza virus infection of mice. In the absence of IFN-γ, lung ILC2s from mice challenged with the A/California/04/2009 (CA04) H1N1 virus, containing nonfunctional viral PB1-F2, initiated a robust IL-5 response, which also led to improved tissue integrity and increased survival. Conversely, challenge with Puerto Rico/8/1934 (PR8) H1N1 virus expressing fully functional PB1-F2, suppressed IL-5
ILC2 responses, and induced a dominant IL-13
CD8 T cell response, regardless of host IFN-γ expression. IFN-γ-deficient mice had increased survival and improved tissue integrity following challenge with lethal doses of CA04, but not PR8 virus, and increased resistance was dependent on the presence of IFN-γR
ILC2s. Reverse-engineered influenza viruses differing in functional PB1-F2 activity induced ILC2 and T cell phenotypes similar to the PB1-F2 donor strains, demonstrating the potent role of viral PB1-F2 in host resistance. These results show the ability of a pathogen virulence factor together with host IFN-γ to regulate protective pulmonary immunity during influenza infection.