TLR7-mediated inflammation drives PD-L1 upregulation and T cell exhaustion during influenza A virus infection
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Date
2026
Authors
Miles, M.A.
Liong, S.
Liong, F.
O'Leary, J.J.
Brooks, D.A.
Selemidis, S.
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iScience, 2026; 29(2):114776-1-114776-20
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Mark A. Miles, Stella Liong, Felicia Liong, John J. O, Leary, Doug A. Brooks, Stavros Selemidis
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Abstract
T cell dysfunction driven by dysregulated programmed cell death-, PD-, 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, TLR, a viral RNA sensor, in regulating PD-, PD-L-mediated T cell responses during IAV infection. Using wild-type and TLR, -deficient mice, we show that TLR, activation enhances early antiviral T cell responses but subsequently increases PD-L, PD-L, 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, TLR, regulated PD-L, expression indirectly via cytokine signaling, rather than directly affecting PD-, expression. These findings identify TLR, as a key upstream modulator of immune checkpoint signaling during IAV infection and suggest that targeting TLR, alone or with checkpoint inhibitors, may boost antiviral immunity and reduce T cell exhaustion.
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© 2026 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).