TLR7-mediated inflammation drives PD-L1 upregulation and T cell exhaustion during influenza A virus infection.

T cell dysfunction driven by dysregulated programmed cell death-1 (PD-1)/PD-ligand (PD-L) immune checkpoint signaling is associated with severe influenza A virus (IAV) infection. While this pathway limits immunopathology, it can suppress antiviral immunity and promote T cell exhaustion. We investigated the role of toll-like receptor 7 (TLR7), a viral RNA sensor, in regulating PD-1/PD-L-mediated T cell responses during IAV infection. Using wild-type and TLR7-deficient mice, we show that TLR7 activation enhances early antiviral T cell responses but subsequently increases PD-L1/PD-L2 expression, promoting T cell exhaustion at later stages of infection. This was associated with higher lung viral loads and increased expression of exhaustion-related genes. Mechanistically, TLR7 regulated PD-L1 expression indirectly via cytokine signaling, rather than directly affecting PD-1 expression. These findings identify TLR7 as a key upstream modulator of immune checkpoint signaling during IAV infection and suggest that targeting TLR7, alone or with checkpoint inhibitors, may boost antiviral immunity and reduce T cell exhaustion.