Cited by 2,070T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersHIV Research and Treatment

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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

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Im, Se Jin, Hashimoto, Masao, Gerner, Michael Y., Lee, Junghwa, Kissick, Haydn T., Burger, Matheus C., Shan, Qiang, Hale, J. Scott, Lee, Judong, Nasti, Tahseen H., Sharpe, Arlene H., Freeman, Gordon J., Germain, Ronald N., Nakaya, Helder I., Xue, Hai-Hui, Ahmed, Rafi·2016·Nature

DOI 10.1038/nature19330PMC PMC5297183

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Abstract

Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (T FH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ T H 1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.

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Authors: Im, S. J., Hashimoto, M., Gerner, M. Y., Lee, J., Kissick, H. T., Burger, M. C., Shan, Q., Hale, J. S., Lee, J., Nasti, T. H., Sharpe, A. H., Freeman, G. J., Germain, R. N., Nakaya, H. I., Xue, H.-H., & Ahmed, R.
Affiliations: Emory University (US)
National Institutes of Health (US)
University of Iowa (US)
Brigham and Women's Hospital (US)
Harvard University (US)
Universidade de São Paulo (BR)
Corresponding author: Ahmed, Rafi
ORCID: Im, Se Jin
Hashimoto, Masao
Gerner, Michael Y.
Lee, Junghwa
Kissick, Haydn T.
Shan, Qiang
Hale, J. Scott
Lee, Judong
Nasti, Tahseen H.
Sharpe, Arlene H.
Freeman, Gordon J.
Germain, Ronald N.
Nakaya, Helder I.
Xue, Hai-Hui
Ahmed, Rafi
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-08-02
Volume: 537
Issue: 7620
Pages: 417-421
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature19330
PMC: PMC5297183
OpenAlex: W2506616866
Cited by: 2,070
References: 37
Citations by year: 2026: 224 · 2025: 245 · 2024: 268 · 2023: 264 · 2022: 248 · 2021: 252 · 2020: 223 · 2019: 154 · 2018: 101 · 2017: 75 · 2016: 13
FWCI: 69.19
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (n01ai30048-10-0-1)
National Institute of Allergy and Infectious Diseases (N01 AI030048, P01AI080192, P01AI056299, R01AI030048, R01AI121080, R01AI112579)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Keywords: CD8+ T cells, PD-1, T cell exhaustion, lymphocytic choriomeningitis virus, chronic viral infection, B cell follicles, T follicular helper cells, PD-L1 blockade, anti-PD-1 therapy, HIV, virus control, costimulatory molecules
MeSH terms: Cell Self Renewal, Animals, Cell Differentiation, Female, T-Lymphocytes, Helper-Inducer, Hematopoietic Stem Cells, Immunotherapy, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, T-Lymphocyte Subsets, CD28 Antigens, CD8-Positive T-Lymphocytes, Cell Proliferation, Mice, Hepatocyte Nuclear Factor 1-alpha, Inducible T-Cell Co-Stimulator Protein, Programmed Cell Death 1 Receptor

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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

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