Acute viral respiratory infection rapidly induces a CD8 T cell exhaustion-like phenotype

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