Highly Pathological Influenza A Virus Infection Is Associated with Augmented Expression of PD-1 by Functionally Compromised Virus-Specific CD8⁺T Cells

Abstract

One question that continues to challenge influenza A research is why some strains of virus are so devastating compared to their more mild counterparts. We approached this question from an immunological perspective, investigating the CD8 ؉ T cell response in a mouse model system comparing high-and low-pathological influenza virus infections. Our findings reveal that the early (day 0 to 5) viral titer was not the determining factor in the outcome of disease. Instead, increased numbers of antigen-specific CD8؉ T cells and elevated effector function on a per-cell basis were found in the low-pathological infection and correlated with reduced illness and latertime-point (day 6 to 10) viral titer. High-pathological infection was associated with increased PD-1 expression on influenza virus-specific CD8؉ T cells, and blockade of PD-L1 in vivo led to reduced virus titers and increased CD8 ؉ T cell numbers in high-but not lowpathological infection, though T cell functionality was not restored. These data show that high-pathological acute influenza virus infection is associated with a dysregulated CD8 ؉ T cell response, which is likely caused by the more highly inflamed airway microenvironment during the early days of infection. Therapeutic approaches specifically aimed at modulating innate airway inflammation may therefore promote efficient CD8 ؉ T cell activity. IMPORTANCEWe show that during a severe influenza virus infection, one type of immune cell, the CD8 T cell, is less abundant and less functional than in a more mild infection. This dysregulated T cell phenotype correlates with a lower rate of virus clearance in the severe infection and is partially regulated by the expression of a suppressive coreceptor called PD-1. Treatment with an antibody that blocks PD-1 improves T cell functionality and increases virus clearance.

Control of pathogenic effector T-cell activities in situ by PD-L1 expression on respiratory inflammatory dendritic cells during respiratory syncytial virus infection

“…These data are in line with recent reports of PD-1 expression on lung T cells during influenza and HMPV infection. 24–26 Interestingly, we further found that PD-1 is highly upregulated on IL-10 producing effector T cells, suggesting that IL-10 and PD-1 expression in T cells may be regulated by the same molecular machinery during RSV infection. Notably, we recently showed that the transcription factor Blimp-1 promoted IL-10 production by effector T cells during influenza infection.…”

“…23 Recently, it was demonstrated that the blockade of PD-1 and PD-L1 interaction in vivo resulted in elevated host effector T-cell responses and enhanced viral clearance during influenza and human metapneumovirus (HMPV) infection, suggesting that PD-1 and PD-L1 may also play a role in restricting effective anti-viral T-cell responses during acute viral infections. 24–26 Similarly, in an in vitro co-culture model, the PD-L1/PD-1 interaction has been shown to inhibit CD8 + T cell effector function when encountering RSV-infected human epithelial cells. 27 However, the exact function of PD-1 and its ligands in vivo during RSV infection, particularly within the respiratory tract, is currently unknown.…”

25-Hydroxycholesterol acts as an amplifier of inflammatory signaling

“…Titers of infectious virus were measured by plaque assay on monolayers of Madin-Darby canine kidney (MDCK) cells as previously described (44).…”

Early Cytokine Dysregulation and Viral Replication Are Associated with Mortality During Lethal Influenza Infection

“…Introduction E ach year, emerging influenza A virus (IAV) infections hospitalize 3-5 million individuals (30), posing a major health threat and significant economic burden worldwide. In addition to circulating seasonal strains, natural IAV infections in zoonotic reservoirs undergo antigenic drift (12,13) and antigenic shift (19) that efficiently evade host immune responses and cause extensive morbidity when transmitted to humans.…”