Proliferating Transitory T Cells with an Effector-like Transcriptional Signature Emerge from PD-1+ Stem-like CD8+ T Cells during Chronic Infection
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T cell dysfunction is a characteristic feature of chronic viral infection and cancer. Recent studies in chronic lymphocytic choriomeningitis virus (LCMV) infection have defined a PD-1+ Tcf-1+ CD8+ T cell subset capable of self-renewal and differentiation into more terminally differentiated cells that downregulate Tcf-1 and express additional inhibitory molecules such as Tim3. Here, we demonstrated that expression of the glycoprotein CD101 divides this terminally differentiated population into two subsets. Stem-like Tcf-1+ CD8+ T cells initially differentiated into a transitory population of CD101-Tim3+ cells that later converted into CD101+ Tim3+ cells. Recently generated CD101-Tim3+ cells proliferated in vivo, contributed to viral control, and were marked by an effector-like transcriptional signature including expression of the chemokine receptor CX3CR1, pro-inflammatory cytokines, and granzyme B. PD-1 pathway blockade increased the numbers of CD101-Tim3+ CD8+ T cells, suggesting that these newly generated transitional cells play a critical role in PD-1-based immunotherapy.
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Progenitor Tex (Tprog) cells retain stemness and self-renewal capacity, respond to immune checkpoint blockade, and differentiate into intermediate T (Tint) cells with cytolytic capacity.
“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 [8]
Terminal Tex (Ttex) cells accumulate over time and respond poorly to immune checkpoint blockade therapies.
“Conversely, terminal Tex (Ttex) cells accumulate over time and respond poorly to ICB therapies8,11–13.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [8]
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- Authors
- Hudson, W. H., Gensheimer, J., Hashimoto, M., Wieland, A., Valanparambil, R. M., Li, P., Lin, J.-X., Konieczny, B. T., Im, S. J., Freeman, G. J., Leonard, W. J., Kissick, H. T., & Ahmed, R.
- Affiliations
- Emory University (US)
- National Institutes of Health (US)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Ahmed, Rafi
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 51
- Issue
- 6
- Pages
- 1043-1058.e4
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6920571
- OpenAlex
- W2991888163
- Cited by
- 656
- References
- 16
- Citations by year
- 2026: 103 · 2025: 122 · 2024: 112 · 2023: 104 · 2022: 83 · 2021: 84 · 2020: 46 · 2019: 2
- FWCI
- 21.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Cancer Research Institute (K99CA197804)
- National Institutes of Health (K99CA197804, R01AI030048, P01AI056299)
- National Cancer Institute
- Center for Outcomes Research and Evaluation, Yale School of Medicine
- Foundation for the National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- 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 › Immunology › Immunotherapy and Immune Responses
- Keywords
- PD-1, CD8+ T cells, TCF1, CD101, TIM-3, chronic viral infection, lymphocytic choriomeningitis virus, T cell differentiation, stem-like T cells, CX3CR1, granzyme B, PD-1 pathway blockade, immunotherapy, T cell dysfunction
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, CX3C Chemokine Receptor 1, Animals, Female, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Male, Mice, Inbred C57BL, Biomarkers, Antigens, CD, CD8-Positive T-Lymphocytes, Mice, Hepatocyte Nuclear Factor 1-alpha, Granzymes, Programmed Cell Death 1 Receptor
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