Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans
Open accessAbstract
T cell memory relies on the generation of antigen-specific progenitors with stem-like properties. However, the identity of these progenitors has remained unclear, precluding a full understanding of the differentiation trajectories that underpin the heterogeneity of antigen-experienced T cells. We used a systematic approach guided by single-cell RNA-sequencing data to map the organizational structure of the human CD8+ memory T cell pool under physiological conditions. We identified two previously unrecognized subsets of clonally, epigenetically, functionally, phenotypically and transcriptionally distinct stem-like CD8+ memory T cells. Progenitors lacking the inhibitory receptors programmed death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) were committed to a functional lineage, whereas progenitors expressing PD-1 and TIGIT were committed to a dysfunctional, exhausted-like lineage. Collectively, these data reveal the existence of parallel differentiation programs in the human CD8+ memory T cell pool, with potentially broad implications for the development of immunotherapies and vaccines.
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The gating strategy shown in this section is applicable for analysis of conventional αβ CD8+ T cells in any kind of physiological or clinical setting.
“The gating strategy shown in this section is applicable for analysis of conventional αβ CD8+ T cells in any kind of physiological or clinical setting [207, 208, 222].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [208]
The Methods (Flow cytometry and cell sorting; page unavailable) describe a conventional gating strategy for CD95+ bulk CD8+ memory T cells. The Methods (Study approval; page unavailable) list healthy donors and patients with cancer or HIV, supporting use across several physiological and clinical contexts. The paper does not establish that the gating strategy shown in the citing section applies to all conventional αβ CD8+ T cells in any setting. (LLM, conf=0.85)
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Targeting the epigenome to reinvigorate T cells for cancer immunotherapy
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- Authors
- Galletti, G., De Simone, G., Mazza, E. M. C., Puccio, S., Mezzanotte, C., Bi, T. M., Davydov, A. N., Metsger, M., Scamardella, E., Alvisi, G., De Paoli, F., Zanon, V., Scarpa, A., Camisa, B., Colombo, F. S., Anselmo, A., Peano, C., Polletti, S., Mavilio, D., Gattinoni, L., Boi, S. K., Youngblood, B. A., Jones, R. E., Baird, D. M., Gostick, E., Llewellyn-Lacey, S., Ladell, K., Price, D. A., Chudakov, D. M., Newell, E. W., Casucci, M., & Lugli, E.
- Affiliations
- IRCCS Humanitas Research Hospital (IT)
- IRCCS Ospedale San Raffaele (IT)
- Fred Hutch Cancer Center (US)
- Central European Institute of Technology (CZ)
- National Research Council (IT)
- Humanitas University (IT)
- University of Milan (IT)
- National Institutes of Health (US)
- St. Jude Children's Research Hospital (US)
- Cardiff University (GB)
- Skolkovo Institute of Science and Technology (RU)
- Corresponding author
- Lugli, Enrico
- ORCID
- Galletti, Giovanni
- Mazza, Emilia M. C.
- Puccio, Simone
- Bi, Timothy M.
- Davydov, Alexey N.
- Metsger, Maria
- Alvisi, Giorgia
- Zanon, Veronica
- Scarpa, Alice
- Camisa, Barbara
- Colombo, Federico S.
- Anselmo, Achille
- Peano, Clelia
- Polletti, Sara
- Mavilio, Domenico
- Gattinoni, Luca
- Boi, Shannon K.
- Youngblood, Benjamin A.
- Baird, Duncan M.
- Ladell, Kristin
- Price, David A.
- Chudakov, Dmitriy M.
- Newell, Evan W.
- Casucci, Monica
- Lugli, Enrico
- Venue
- Nature Immunology
- Published
- 2020-10-12
- Volume
- 21
- Issue
- 12
- Pages
- 1552-1562
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC7610790
- OpenAlex
- W3092341078
- Cited by
- 299
- References
- 74
- Citations by year
- 2026: 31 · 2025: 49 · 2024: 66 · 2023: 53 · 2022: 51 · 2021: 46 · 2020: 3
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion)
- Funders
- Wellcome Trust (100326, 100326/Z/12/Z)
- Cancer Research UK (C17199/A18246/A29202, 29202, 18246)
- 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
- memory CD8+ T cells, T cell exhaustion, PD-1, TIGIT, T cell differentiation, inhibitory receptors, single-cell RNA sequencing
- MeSH terms
- Animals, Cell Differentiation, Humans, Immunologic Memory, Biomarkers, Immunophenotyping, T-Lymphocyte Subsets, CD8-Positive T-Lymphocytes, Computational Biology, Gene Expression Profiling, Mice, Lymphoid Progenitor Cells, High-Throughput Nucleotide Sequencing, Telomere Homeostasis
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