Acute Viral Respiratory Infection Rapidly Induces a CD8+ T Cell Exhaustion–like Phenotype

Abstract

Acute viral infections typically generate functional effector CD8+ T cells (TCD8) that aid in pathogen clearance. However, during acute viral lower respiratory infection (LRI), lung TCD8 are functionally impaired and do not optimally control viral replication. T cells also become unresponsive to antigen during chronic infections and cancer via signaling by inhibitory receptors like programmed cell death-1 (PD-1). PD-1 also contributes to TCD8 impairment during viral LRI, but how it regulates TCD8 impairment and the connection between this state and T cell exhaustion during chronic infections is unknown. Here we show that PD-1 operates in a cell-intrinsic manner to impair lung TCD8. In light of this, we compared global gene expression profiles of impaired epitope-specific lung TCD8 to functional spleen TCD8 in the same human metapneumovirus (HMPV)-infected mice. These two populations differentially regulate hundreds of genes, including the upregulation of numerous inhibitory receptors by lung TCD8. We then compared the gene expression of TCD8 during HMPV infection to those in acute or chronic LCMV infection. We find that the immunophenotype of lung TCD8 more closely resembles T cell exhaustion late into chronic infection than functional effector T cells arising early in acute infection. Finally, we demonstrate that trafficking to the infected lung alone is insufficient for TCD8 impairment or inhibitory receptor upregulation, but that viral antigen-induced TCR signaling is also required. Our results indicate that viral antigen in infected lungs rapidly induces an exhaustion-like state in lung TCD8, characterized by progressive functional impairment and upregulation of numerous inhibitory receptors.

Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection

“…This is in contrast to splenic or draining lymph node T CD8 , which maintain functionality during respiratory viral infection (19–24, 38). Here, we confirmed that splenic T CD8 remain functional at later time points; we focused on splenic T CD8 because transcriptome analyses showed significant differential gene regulation between lung and spleen T CD8 (45). Moreover, there were insufficient numbers of cells in the draining lymph nodes during HMPV infection to perform ex vivo tetramer and ICS assays (data not shown).…”

“…Gene expression analysis of lung and spleen T CD8 revealed that numerous immunomodulatory receptors were upregulated by lung T CD8 during acute viral LRI (45). To determine whether some of these inhibitory receptors increased on the cell surface during acute viral LRI, we performed flow cytometric analysis of lung and spleen HMPV-specific T CD8 at days 7, 10, and 14 p.i.…”

Persistence in Temporary Lung Niches: A Survival Strategy of Lung-Resident Memory CD8+T Cells

“…Thus, the level of residual antigen presentation must be lower than that exhibited during a typical chronic infection. In line with this, PD-1 as well as other potential inhibitory molecules may act to prevent excessive immunopathology (26,27,29) by maintaining the cells in a quiescent state (49). Furthermore, reactivation of CD8 + T RM cells in the lung leads to sustained expression of interferon-induced transmembrane protein (IFITM3), which is involved in conferring resistance against subsequent virus infection (132).…”

Modulation of Host Immunity by the Human Metapneumovirus

“…Erickson and coworkers recently extended the understanding of the mechanisms responsible for impaired CTL responses in the respiratory tract of mice acutely infected with HMPV. They demonstrated that upon antigen recognition in the lungs, CD8 ϩ T cells rapidly become exhausted due to the upregulation of PD-1 and other inhibitory receptors (223). Therefore, the infection-generated immunological milieu appears to dampen the efficient clearance of HMPV in vivo.…”

“…Animal studies have contributed enormously to the preclinical evaluation of vaccine candidates and helped in the identification of immunological mechanisms that confer immunity against experimental infections (summarized in Table 1) (85,91,97,103,126,227,229,230,(232)(233)(234)(235)(236)(237)(238)(239). At the molecular level, the mouse model of infection has yielded the majority of evidence regarding potential pathophysiological mechanisms related to HMPV lung disease (132,138,148,159,160,220,223,240,241). Despite this body of information, however, a debate has been raised regarding the usefulness of the mouse model in understanding the response of humans against HMPV.…”