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

TL;DR

This study shows that TLR7, a virus sensor, increases inflammation during flu, leading to T cell exhaustion and reduced immunity.

Contribution

The study reveals TLR7 as a key driver of PD-L1/PD-L2 expression and T cell dysfunction during influenza.

Findings

TLR7 enhances early T cell responses but later increases PD-L1/PD-L2 expression and T cell exhaustion.

TLR7 regulates PD-L1 expression through cytokine signaling, not directly on T cells.

TLR7 deficiency reduces checkpoint signaling and improves antiviral T cell function.

Abstract

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.

•During IAV infection, TLR7 drives cytokine-dependent PD-L1 and PD-L2 expression•TLR7 boosts early T cell activation but promotes later checkpoint-mediated dysfunction•TLR7-induced PD-L expression is inflammatory-driven, not T cell-intrinsic•TLR7 deficiency limits checkpoint signaling and preserves antiviral T cell function

During IAV infection, TLR7 drives cytokine-dependent PD-L1 and PD-L2 expression

TLR7 boosts early T cell activation but promotes later checkpoint-mediated dysfunction

TLR7-induced PD-L expression is inflammatory-driven, not T cell-intrinsic

TLR7 deficiency limits checkpoint signaling and preserves antiviral T cell function

Biochemistry; cell biology; cancer

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