The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection

The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory follo...

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Published in:Cell reports (Cambridge) Vol. 31; no. 13; p. 107827
Main Authors: Pauken, Kristen E., Godec, Jernej, Odorizzi, Pamela M., Brown, Keturah E., Yates, Kathleen B., Ngiow, Shin Foong, Burke, Kelly P., Maleri, Seth, Grande, Shannon M., Francisco, Loise M., Ali, Mohammed-Alkhatim, Imam, Sabrina, Freeman, Gordon J., Haining, W. Nicholas, Wherry, E. John, Sharpe, Arlene H.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 30.06.2020
Elsevier
Subjects:
acute infection
Administration, Intranasal
Animals
CD8+ T cell
CD8-Positive T-Lymphocytes - immunology
Cell Death - immunology
Cell Differentiation - immunology
Cell Proliferation
checkpoint blockade
effector
Immunologic Memory
influenza
Influenza A Virus, H3N2 Subtype - physiology
memory
Mice, Inbred C57BL
Orthomyxoviridae Infections - immunology
Orthomyxoviridae Infections - pathology
Orthomyxoviridae Infections - virology
PD-1
PD-L1
PD-L2
Programmed Cell Death 1 Receptor - metabolism
Signal Transduction
Species Specificity
influenza
checkpoint blockade
memory
acute infection
PD-L1
PD-L2
effector
PD-1
CD8+ T cell
CD8(+) T cell
ISSN:2211-1247, 2211-1247
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Summary:The PD-1 pathway regulates dysfunctional T cells in chronic infection and cancer, but the role of this pathway during acute infection remains less clear. Here, we demonstrate that PD-1 signals are needed for optimal memory. Mice deficient in the PD-1 pathway exhibit impaired CD8+ T cell memory following acute influenza infection, including reduced virus-specific CD8+ T cell numbers and compromised recall responses. PD-1 blockade during priming leads to similar differences early post-infection but without the defect in memory formation, suggesting that timing and/or duration of PD-1 blockade could be tailored to modulate host responses. Our studies reveal a role for PD-1 as an integrator of CD8+ T cell signals that promotes CD8+ T cell memory formation and suggest PD-1 continues to fine-tune CD8+ T cells after they migrate into non-lymphoid tissues. These findings have important implications for PD-1-based immunotherapy, in which PD-1 inhibition may influence memory responses in patients. [Display omitted] •Early loss of PD-1 leads to overactivation of CD8+ T cells during acute infection•Mice constitutively lacking PD-1 or PD-L develop impaired CD8+ T cell memory•Cell-intrinsic PD-1 signals suppress effector cell expansion and promote memory•Timing of PD-1 blockade determines impact on memory generation The role of PD-1 in memory development is poorly understood. Here, Pauken et al. show that constitutive loss of PD-1 during acute infection causes overactivation of CD8+ T cells during the effector phase and impairs memory and recall responses. These data indicate PD-1 is required for optimal memory.
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AUTHOR CONTRIBUTIONS
K.E.P., J.G., P.M.O., K.E.B., E.J.W., and A.H.S. conceived the studies. K.E.P., J.G., P.M.O., K.E.B., M.-A.A., S.F.N., K.P.B., and S.M. performed experiments and generated primary data, including developing methodology, validation, and data curation. K.E.P., J.G., P.M.O., and K.E.B. performed formal analysis and visualization. S.M.G., L.M.F., and M.-A.A. assisted in animal colony maintenance and performing some mouse experiments. K.B.Y., S.I., and W.N.H. performed and analyzed transcriptional profiling data. K.E.P., J.G., P.M.O., K.E.B., G.J.F., E.J.W., and A.H.S. contributed to writing the manuscript. All authors contributed to reviewing and editing the final manuscript. E.J.W. and A.H.S. were responsible for project supervision, administration, and funding acquisition.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2020.107827