Viral acute lower respiratory infections impair CD8+ T cells through PD-1

Abstract

Viruses are leading causes of severe acute lower respiratory infections (LRIs). These infections evoke incomplete immunity, as individuals can be repeatedly reinfected throughout life. We report that acute viral LRI causes rapid pulmonary CD8 + cytotoxic T lymphocyte (T CD8 ) functional impairment via programmed death-1/ programmed death ligand-1 (PD-1/PD-L1) signaling, a pathway previously associated with prolonged antigenic stimulation during chronic infections and cancer. PD-1-mediated T CD8 impairment occurred acutely in mice following infection with human metapneumovirus or influenza virus. Viral antigen was sufficient for PD-1 upregulation, but induction of PD-L1 was required for impairment. During secondary viral infection or epitope-only challenge, memory T CD8 rapidly reexpressed PD-1 and exhibited severe functional impairment. Inhibition of PD-1 signaling using monoclonal antibody blockade prevented T CD8 impairment, reduced viral titers during primary infection, and enhanced protection of immunized mice against challenge infection. Additionally, PD-1 and PD-L1 were upregulated in the lungs of patients with 2009 H1N1 influenza virus, respiratory syncytial virus, or parainfluenza virus infection. These results indicate that PD-1 mediates T CD8 functional impairment during acute viral infection and may contribute to recurrent viral LRIs. Therefore, the PD-1/PD-L1 pathway may represent a therapeutic target in the treatment of respiratory viruses.

Local Blockade of Epithelial PDL-1 in the Airways Enhances T Cell Function and Viral Clearance during Influenza Virus Infection

“…Our study builds on the observations by Erickson et al (27) to further show that PDL-1 is constitutively expressed in airway epithelial cells and its expression is upregulated by influenza virus and dependent on interferon alpha receptor (IFNAR) signaling. Coculture studies with airway epithelial cells and T cells in the presence of PDL-1 blocking antibody revealed that PDL-1 expression on airway epithelial cells repressed T cell function.…”

“…The role of PD-1-expressing T cells during acute infection has remained controversial (39), although recent observations report increased primary T cell responses in the absence of PD-1 signaling (25,27,40). Additionally, a recent study showed that the majority of PD-1-expressing T cells in healthy human adults do not exhibit an exhausted phenotype (41).…”

“…PD-1 has also been shown to regulate the development of T cell memory during vaccinia virus infection (25). Fairly recently, it has been shown that a number of acute respiratory viral infections, including human metapneumovirus, respiratory syncytial virus, and influenza virus, impair CD8 T cell function through PD-1 (26) (27). Although previous studies have shown that lack of PD-1 function due to genetic mutation or to systemic blockade prevented CD8 T cell inhibition and enhanced viral control, the specific role that the airway epithelium plays during PDL-1/PD-1 regulation of pulmonary T cell function has not been fully elucidated.…”

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…Similarly, impairment of CD8 C T cells was prevented on hMPV-infected PD-1¡/¡ mice. 152 In other studies, an impairment of lung hMPV-specific memory CD8 C T cells was observed in mMT mice, which lack B-cells and are used as a model for hMPV reinfection, which suggest the importance of memory CD8 C T cells in viral clearance during a second infection. 153 Specifically, during reinfection, CD8 C T cells had upregulated several inhibitory receptors, including PD-1.…”

“…151 Additionally, CD8 C T cells can be impaired by hMPV in a PD-1 dependent manner, similar to hRSV, as lung CD8 C T cells are impaired in HLA B7.2 transgenic (B7tg) mice and had upregulated PD-1. 152 Conversely, blocking of PD-1 by administration of monoclonal specific antibodies in B7tg mice prevented the CD8 C T cells impairment. Similarly, impairment of CD8 C T cells was prevented on hMPV-infected PD-1¡/¡ mice.…”