Local blockade of epithelial PDL-1 in the airways enhances T cell function and viral clearance during influenza virus infection.
In order to maintain the gas exchange function of the lung following influenza virus infection, a delicate orchestration of positive and negative regulatory pathways must be maintained to attain viral eradication while minimizing local inflammation. The programmed death receptor 1 ligand/programmed death receptor 1 (PDL-1/PD-1) pathway plays an important immunoregulatory role, particularly in the context of T cell function. Here, we have shown that influenza virus infection of primary airway epithelial cells strongly enhances PDL-1 expression and does so in an alpha interferon receptor (IFNAR) signaling-dependent manner. PD-1 is expressed primarily on effector T cells in the lung, compared to effector memory and central memory cells, and shortly after influenza virus infection, an increased number of PD-1(+) T cells are recruited to the airways. Using in vitro cocultures of airway epithelial cells and T cells and in vivo models of influenza virus infection, we have demonstrated that blockade of airway epithelial PDL-1 improves CD8 T cell function, defined by increased production of gamma interferon (IFN-γ) and granzyme B and expression of CD107ab. Furthermore, PDL-1 blockade in the airways served to accelerate influenza virus clearance and enhance infection recovery. Our findings suggest that local manipulation of the PDL-1/PD-1 axis in the airways may represent a therapeutic alternative during acute influenza virus infection.
Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
Beth
B
McNally
Fang
F
Ye
Meredith
M
Willette
Emilio
E
Flaño
D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology* / Q000821:virology; D005260:Female; D006801:Humans; D009980:Influenza A virus / Q000276:immunology / Q000502:physiology*; D007251:Influenza, Human / Q000276:immunology* / Q000821:virology; D007371:Interferon-gamma / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000821:virology; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology*; D014132:Trachea / Q000166:cytology* / Q000276:immunology / Q000821:virology
D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007371:Interferon-gamma