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The who's who of T ‐cell differentiation: Human memory T ‐cell subsets
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Following antigen encounter and subsequent resolution of the immune response, a single naïve T cell is able to generate multiple subsets of memory T cells with different phenotypic and functional properties and gene expression profiles. Single‐cell technologies, first and foremost flow cytometry, have revealed the complex heterogeneity of the memory T ‐cell compartment and its organization into subsets. However, a consensus has still to be reached, both at the semantic (nomenclature) and phenotypic level, regarding the identification of these subsets. Here, we review recent developments in the characterization of the heterogeneity of the memory T ‐cell compartment, and propose a unified classification of both human and nonhuman primate T cells on the basis of phenotypic traits and in vivo properties. Given that vaccine studies and adoptive cell transfer immunotherapy protocols are influenced by these recent findings, it is important to use uniform methods for identifying and discussing functionally distinct subsets of T cells.
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“Multidimensional flow cytometry with up to 40 parameters enables a deeper phenotyping and characterization of the immune system, which is required as cellular subsets require more and more markers for accurate definition [81].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [81]
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“Moreover, by tSNE, we confirmed that TCMs further differentiated into transitional memory T cells (TTMs) in vitro during viral outgrowth (Figures 4C and 4D) as a logical consequence after stimulation.”
From Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods (2023) · cites this paper as [51]
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“The patient showed increased number of CD8 + T cells, which showed a more activated and differentiated phenotype as indicated by an elevated proportion of HLA-DR + or CD38 + cells (7).”
From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [7]
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“a small population of memory T cells endowed with elevated proliferative and self-renewal capacities has been identified within the CD45RA+CCR7+ naïve T-cell gate. These cells have been termed stem cell-like memory (Tscm) cells [140] and can be distinguished from truly naïve T cells based on the expression of the FAS receptor (CD95) (Figure 8A) [81].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [81]
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“Both the CD4 + and CD8 + T-cell subsets displayed a signi cantly lower proportion of CD28 + cells, suggesting a decrease in naïve T cell which express a high level of differentiation marker CD28 (7).”
From A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections (2024) · cites this paper as [7]
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Antioxidant metabolism regulates CD8+ T memory stem cell formation and antitumor immunity
Pilipow, K., Scamardella, E., Puccio, S., Gautam, S., Paoli, F. D., Mazza, E. M. C., Simone, G. D., Polletti, S., Buccilli, M., Zanon, V., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.122299 · Cited by 136
“In accordance with such increased relative frequency of early differentiated memory phenotypes and with human data, NAC-treated Cor93-specific CD8 + T cells produced less IFN-γ but similar amounts of TNF compared with control cells at day 35 after ACT when restimulated with the cognate peptide in vitro (Figure 5H).”
InfluentialSelf-citationWeltevrede, M., Eilers, R., de Melker, H. E., & van Baarle, D. (2016) · Experimental Gerontology · doi:10.1016/j.exger.2016.02.005 · Cited by 128
“Based on their functionality and the expression of different surface markers memory T cells can be found in several different stages of differentiation (8-11).”
MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation
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Highly differentiated cytotoxic T cells in inclusion body myositis
Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher‐Allan, C., Amato, A. A., & Dorfman, D. M. (2019) · Brain · doi:10.1093/brain/awz207 · Cited by 125
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TCF1 expression marks self-renewing human CD8+ T cells
Kratchmarov, R., Magun, A. M., & Reiner, S. L. (2018) · Blood Advances · doi:10.1182/bloodadvances.2018016279 · Cited by 116
“TCM cells retain a greater proliferative capacity than TEM cells but exhibit less function immediately after restimulation.(1) TEMRA cells are thought to be terminally differentiated.”
BackgroundNanomedicine-based drug delivery towards tumor biological and immunological microenvironment
Li, J., & Burgess, D. J. (2020) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2020.05.008 · Cited by 118
Features of Effective T Cell-Inducing Vaccines against Chronic Viral Infections
Panagioti, E., Klenerman, P., Lee, L. N., van der Burg, S. H., & Arens, R. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00276 · Cited by 106
Immunological memories of the bone marrow
Chang, H., Tokoyoda, K., & Radbruch, A. (2018) · Immunological Reviews · doi:10.1111/imr.12656 · Cited by 113
de Weerdt, I., Hofland, T., de Boer, R., Dobber, J. A., Dubois, J., van Nieuwenhuize, D., Mobasher, M., de Boer, F., Hoogendoorn, M., Velders, G. A., et al. (2019) · Blood Advances · doi:10.1182/bloodadvances.2019000360 · Cited by 110
“effector memory T cells based on CD27 and CD45RA expression.(43) Although the differentiation status of CD4(1) T cells did not differ between LN and PB in CLL patients and HCs, the CD8(1) compartment in CLL patients consisted of a larger proportion of central memory T cells in the LN in comparison with the PB (37.”
ResultThe Single-Cell Phenotypic Identity of Human CD8+ and CD4+ T Cells
Brummelman, J., Pilipow, K., & Lugli, E. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.05.007 · Cited by 113
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Memory T Cells Expressing an NKG2D-CAR Efficiently Target Osteosarcoma Cells
Fernández, L., Metais, J.-Y., Escudero, A., Vela, M., Valentín, J., Vallcorba, I., Leivas, A., Torres, J., Valeri, A., Patiño-García, A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-0075 · Cited by 108
“CD45RA is expressed on na€ ve T cells, whereas CD45RO is expressed on memory T cells (22).”
BackgroundStem, Effector, and Hybrid States of Memory CD8+ T Cells
Lugli, E., Galletti, G., Boi, S. K., & Youngblood, B. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.11.004 · Cited by 107
“Specifically, in recent work, our group examined wholegenome DNA methylation from cell-sorted memory CD8+ T cell subsets isolated from the blood of healthy human donors: the analysis revealed genes that were differentially targeted for methylation programming between TEM and TSCM cells, and which were enriched in path…”
BackgroundInfluentialSelf-citationMolecular Aspects and Future Perspectives of Cytokine-Based Anti-cancer Immunotherapy
Chulpanova, D. S., Kitaeva, K. V., Green, A. R., Rizvanov, A. A., & Solovyeva, V. V. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00402 · Cited by 112
Immunopathology of RSV: An Updated Review
Bergeron, H. C., & Tripp, R. A. (2021) · Viruses · doi:10.3390/v13122478 · Cited by 116
Loschinski, R., Böttcher, M., Stoll, A., Bruns, H., Mackensen, A., & Mougiakakos, D. (2018) · Oncotarget · doi:10.18632/oncotarget.24442 · Cited by 109
“Overall, all tested immunometabolic parameters point towards promotion of memory T-cells by IL-21, which we confirmed by the according phenotypical analyses [48].”
ResultHuman CD8+ CD57- TEMRA cells: Too young to be called "old"
Verma, K., Ogonek, J., Varanasi, P. R., Luther, S., Bünting, I., Thomay, K., Behrens, Y. L., Weissinger, E. M., & Hambach, L. (2017) · PLoS ONE · doi:10.1371/journal.pone.0177405 · Cited by 105
Increased CD95 (Fas) and PD‐1 expression in peripheral blood T lymphocytes in COVID‐19 patients
Bellesi, S., Metafuni, E., Hohaus, S., Maiolo, E., Marchionni, F., D’Innocenzo, S., Sorda, M. L., Ferraironi, M., Ramundo, F., Fantoni, M., et al. (2020) · British Journal of Haematology · doi:10.1111/bjh.17034 · Cited by 102
“CD95 is widely expressed in Memory and Effector T cells upon contact with antigen, while Naive T cells are typically CD95 negative.(7,8) Programmed cell death 1 (PD-1, CD279), an antigen of Effector T cells, is considered an exhaustion marker, also expressed during antigen-mediated T cell activation.”
BackgroundPeripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors
An, H. J., Chon, H. J., & Kim, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179414 · Cited by 107
“WistubaHamprecht et al. demonstrated that high frequencies of CD8 effector-memory type 1 T cells defined as CD45 RA− CCR7− CD27+ CD28+ in the peripheral blood within 4 weeks of treatment initiation were associated with higher clinical response and longer OS [37].”
BackgroundA shift in lung macrophage composition is associated with COVID-19 severity and recovery
Chen, S. T., Park, M. D., Valle, D. M. D., Buckup, M., Tabachnikova, A., Thompson, R. C., Simons, N. W., Mouskas, K., Lee, B. H., Geanon, D., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abn5168 · Cited by 106
“S8, C to E) (24, 25).”
Lieber, S., Reinartz, S., Raifer, H., Finkernagel, F., Dreyer, T. F., Bronger, H., Jansen, J. M., Wagner, U. A. G., Worzfeld, T., Müller, R., et al. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1424672 · Cited by 103
“1D) is consistent with the known properties of CD8C TEM cells, including high cytotoxic activity and rapid effector cytokine production.(29) Therefore, we focused on the mechanisms of CD8C TEM cell migration and activation in ovarian carcinoma ascites.”
BackgroundRapidly Switchable Universal CAR-T Cells for Treatment of CD123-Positive Leukemia
Loff, S., Dietrich, J., Meyer, J.-E., Riewaldt, J., Spehr, J., Bonin, M. V., Gründer, C., Swayampakula, M., Franke, K., Feldmann, A., et al. (2020) · Molecular Therapy — Oncolytics · doi:10.1016/j.omto.2020.04.009 · Cited by 104
Memory T-Cell Heterogeneity and TerminologyPreprint
Muroyama, Y., & Wherry, E. J. (2021) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a037929 · Cited by 104
Grau-Expósito, J., Serra‐Peinado, C., Miguel-Escuder, L., Navarro, J., Curran, A., Burgos, J., Ocaña, I., Ribera, E., Torrella, A., Planas, B., et al. (2017) · mBio · doi:10.1128/mbio.00876-17 · Cited by 100
“Of note, identification of effector memory CD4 T cells was carried out by using the phenotypic markers CD45RO and CCR7, and therefore, this population can also contain cells with a transitional memory phenotype (53).”
MethodSouto‐Carneiro, M., Klika, K. D., Abreu, M., Meyer, A. P., Saffrich, R., Sandhoff, R., Jennemann, R., Kraus, F. V., Tykocinski, L., Eckstein, V., et al. (2020) · Arthritis & Rheumatology · doi:10.1002/art.41420 · Cited by 107
“Since naive RA CD8+ T cells presented metabolic and enzymatic profiles that were similar to those of antigen-experienced T cell subsets, we pondered whether the CD45RA+CCR7+ compartment of RA CD8+ T cells could also include CD95expressing stem-cell memory T cells (30), which could account for their profile resembling…”
BackgroundGeyer, M. B., Rivière, I., Sénéchal, B., Wang, X., Wang, Y., Purdon, T. J., Hsu, M., Devlin, S. M., Palomba, M. L., Halton, E. F., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.122627 · Cited by 100
Froghi, S., Grant, C. R., Tandon, R., Quaglia, A., Davidson, B. R., & Fuller, B. J. (2021) · Clinical Reviews in Allergy & Immunology · doi:10.1007/s12016-020-08824-3 · Cited by 98
“TRPM4 exerted this effect via membrane depolarisation, which limits the driving force for Ca2+ entry via the CRAC channel [187].”
BackgroundInfluentialGuo, M., Bafligil, C., Tapmeier, T. T., Hubbard, C., Manek, S., Shang, C. A., Martínez, F. O., Schmidt, N., Obendorf, M., Hess‐Stumpp, H., et al. (2020) · BMC Medicine · doi:10.1186/s12916-019-1470-y · Cited by 96
Accelerated aging with HIV occurs at the time of initial HIV infection
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van der Burg, M., Kalina, T., Pérez‐Andrés, M., Vlková, M., López‐Granados, E., Blanco, E., Bonroy, C., Sousa, A. E., Kienzler, A., Wentink, M. W. J., et al. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00246 · Cited by 95
Systemic CD4 Immunity as a Key Contributor to PD-L1/PD-1 Blockade Immunotherapy Efficacy
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Zwijnenburg, A. J., Pokharel, J., Varnaitė, R., Zheng, W., Hoffer, E., Shryki, I., Comet, N. R., Ehrström, M., Gredmark‐Russ, S., Eidsmo, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.06.025 · Cited by 92
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Progesterone Modulation of Pregnancy-Related Immune Responses
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The secret life of ion channels: Kv1.3 potassium channels and proliferation
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“CCR7 + cells are named central memory T-cells (T CM ) because of their location in secondary lymphoid tissues, while CCR7 - cells were named effector memory (T EM ) because of their rapid effector function ex-vivo (106).”
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“In addition, Ikaros has been shown to alter the threshold for activation of T cells downstream of T cell receptor and IL2 receptor signaling as well as protein kinase C, PI3K, and calcineurin signaling (22).”
BackgroundInfluentialCirculating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
Biasi, S. D., Gibellini, L., Tartaro, D. L., Puccio, S., Rabacchi, C., Mazza, E. M. C., Brummelman, J., Williams, B., Kaihara, K. A., Forcato, M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21928-4 · Cited by 89
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Coordinated Regulation of NK Receptor Expression in the Maturing Human Immune System
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“maturation, many leukocytes develop into distinct subsets whose diversity correlates with vast functional heterogeneity (1).”
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T Cell–Macrophage Interactions and Granuloma Formation in Vasculitis
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Reproducibility of Flow Cytometry Through Standardization: Opportunities and Challenges
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“In the immunology field, the expansion of the number of functional subsets revealed by expanding the number of available parameters led to a need for consensus on which set of markers could be used to define and thus enumerate different cell subsets (46,47).”
BackgroundAdaptive immune responses to SARS-CoV-2 persist in the pharyngeal lymphoid tissue of children
Xu, Q., Milanez‐Almeida, P., Martins, A. J., Radtke, A. J., Hoehn, K. B., Oguz, C., Chen, J., Liu, C., Tang, J., Grubbs, G., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01367-z · Cited by 82
Metadata
- Authors
- Mahnke, Y. D., Brodie, T. M., Sallusto, F., Roederer, M., & Lugli, E.
- Affiliations
- University of Pennsylvania (US)
- Institute for Research in Biomedicine (CH)
- National Institutes of Health (US)
- Humanitas University (IT)
- Corresponding author
- Roederer, Mario
- Lugli, Enrico
- Venue
- European Journal of Immunology
- Publisher
- Wiley
- Published
- 2013-10-30
- Volume
- 43
- Issue
- 11
- Pages
- 2797-2809
- ISSN
- 0014-2980 (ISSN-L)
- 1521-4141
- OpenAlex
- W1572743872
- Cited by
- 817
- References
- 113
- Citations by year
- 2026: 25 · 2025: 42 · 2024: 64 · 2023: 76 · 2022: 100 · 2021: 93 · 2020: 105 · 2019: 81 · 2018: 71 · 2017: 53 · 2016: 37 · 2015: 39 · 2014: 28 · 2013: 1
- FWCI
- 3.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Funders
- National Science Foundation
- European Commission (241745, 322093)
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (131092)
- Fondazione Cariplo (2012-0683)
- Associazione Italiana per la Ricerca sul Cancro
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- FP7 Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- memory T cells, T cell differentiation, T cell memory subsets, T cell heterogeneity, T cell phenotype, vaccine immunology, adoptive cell transfer, single-cell technologies
- MeSH terms
- Cell Differentiation, Humans, Immunologic Memory, Lymphocyte Activation, Gene Expression, T-Lymphocyte Subsets, Immunotherapy, Adoptive, Adoptive Transfer
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