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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
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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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“Progenitor Tex (Tprog) cells retain stemness and self-renewal capacity that respond to immune checkpoint blockade (ICB) therapies and differentiate into intermediate T (Tint) cells with cytolytic capacity8–10.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [10]
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“Two recent studies have shown that it is indeed CD28-expressing cells rather than already terminally differentiated effector cells that respond to PD-1 blockade with a proliferative burst and differentiation (94, 95).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [94]
In the citing paper
“Preclinical models demonstrated that PD-1 blockade results in tumor rejection through reinvigoration of exhausted CD8 T cells that express PD-1, LAG3, and TIM3 and expansion of CD8 T cells, a hallmark of response to anti-PD-1 therapy (16).”
From The Next Decade of Immune Checkpoint Therapy (2021) · cites this paper as [16]
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Metadata
- 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
- Venue
- Nature
- Published
- 2016-08-02
- Volume
- 537
- Issue
- 7620
- Pages
- 417-421
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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