Phenotype and function of human T lymphocyte subsets: Consensus and issues
Open accessAbstract
In recent years, a tremendous effort has been devoted to the detailed characterization of the phenotype and function of distinct T cell subpopulations in humans, as well as to their pathway(s) of differentiation and role in immune responses. But these studies seem to have generated more questions than definitive answers. To clarify issues related to the function and differentiation of T cell subsets, one session of the MASIR 2008 conference was dedicated to this topic. Several points of consensus and discord were highlighted in the work presented during this session. We provide here an account of these points, including the relative heterogeneity of T cell subpopulations during infections with distinct pathogens, the relationship between phenotypic and functional T cell attributes, and the pathway(s) of T cell differentiation. Finally, we discuss the problems which still limit general agreement. Published 2008 Wiley‐Liss, Inc.
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These cells re-express CD45RA in combination with markers often stated to reflect 'senescence' such as CD57 and KLRG1.
“Further, these cells re-express CD45RA in combination with markers often stated to reflect “senescence” such as CD57 and KLRG1 (Appay et al. 2008; van Lier et al. 2003).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Appay et al. 2008
CMV-specific T cells exhibit a late-stage differentiated phenotype, including loss of co-stimulatory molecules (e.g., CD27 and CD28) and cell-surface proteins associated with homing to lymphoid tissue (e.g., CD62L and CCR7).
“These CMV-specific T cells exhibit a late-stage differentiated phenotype, including loss of co-stimulatory molecules (e.g., CD27 and CD28) and cell-surface proteins associated with homing to lymphoid tissue (e.g., CD62L and CCR7) (Appay et al. 2008; van Lier et al. 2003).”
From Is immunosenescence influenced by our lifetime “dose” of exercise? (2016) · cites this paper as Appay et al. 2008
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“Constitutive CD27/CD70 interaction induces expansion of effector-type T cells and results in IFNgamma-mediated B cell depletion.”
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Self-citationThe Activatory Receptor 2B4 Is Expressed In Vivo by Human CD8+ Effector αβ T Cells
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Ex Vivo Phenotype and Frequency of Influenza Virus-Specific CD4 Memory T Cells
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Tussey, L., Nair, U. S., Bachinsky, M., Edwards, B. H., Bakari, J., Grimm, K. M., Joyce, J. G., Vessey, R., Steigbigel, R. T., Robertson, M. N., et al. (2003) · The Journal of Infectious Diseases · doi:10.1086/367707 · Cited by 64 · see citing works
He, X.-S., Mahmood, K., Maecker, H. T., Holmes, T. H., Kemble, G. W., Arvin, A. M., & Greenberg, H. B. (2003) · The Journal of Infectious Diseases · doi:10.1086/368218 · Cited by 63 · cited 3× · see citing works
“Following the infection with cleared viruses such as influenza or RSV, virus-specific CD8 T cells appear predominantly CCR71CD271CD281 (34,35).”
BackgroundSun, Y., Schmitz, J. E., Buzby, A. P., Barker, B. R., Rao, S. S., Xu, L., Yang, Z., Mascola, J. R., Nabel, G. J., & Letvin, N. L. (2006) · Journal of Virology · doi:10.1128/jvi.01458-06 · Cited by 60 · see citing works
Chattopadhyay, P. K., Melenhorst, J. J., Ladell, K., Emma Gostick, D., Scheinberg, P., Barrett, A. J., Wooldridge, L., Roederer, M., Sewell, A. K., & Price, D. A. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20642 · Cited by 56 · cited 1× · see citing works
“Techniques that allow satisfactory detection of subdominant or low avidity CD81 T cell populations (see the article by Price and coworkers (72) in the present issue of Cytometry) will help us understanding the true role of these cells, which is often overlooked.”
BackgroundSelf-citationCombadière, B., Faure, S., Autran, B., Debré, P., & Combadière, C. (2003) · AIDS · doi:10.1097/00002030-200306130-00002 · Cited by 50 · cited 4× · see citing works
“In addition, the expression of some chemokine receptors (e.g., CCR7 and CX3CR1) (4,17) as well as adhesion molecules (e.g., CD11a and CD62L) also seem to follow a common pattern.”
BackgroundInfluentialMeier, S., Stark, R., Frentsch, M., & Thiel, A. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20640 · Cited by 43 · cited 1× · see citing works
“(see the articles by Casorati and coworkers (74) or Thiel and coworkers (75), respectively.”
BackgroundAppay, V., Bosio, A., Lokan, S., Wiencek, Y., Biervert, C., Küsters, D., Devêvre, E., Speiser, D. E., Romero, P. J., Rufer, N., et al. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.11.7406 · Cited by 41 · cited 1× · see citing works
“emerge between CD8 and CD4 T cells, in terms of phenotype, functional attributes, telomere shortening as well as gene expression profiles (43,59,60).”
BackgroundSelf-citationHow flow cytometry is changing the study of TB immunology and clinical diagnosis
Fuhrmann, S., Streitz, M., & Kern, F. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20614 · Cited by 39 · cited 1× · see citing works
“New insights into CD41 T cell subset differentiation and function (as proposed by Kern and coworkers (73) in the case of Mycobacterium tuberculosis infection) implies the use of improved methods to identify accurately antigen specific CD41 T cells; these include the use of MHC Class II tetramers or CD154 analysis”
MethodFunctional re-expression of CCR7 on CMV-specific CD8+ T cells upon antigenic stimulation
van Leeuwen, E. M. M., van Buul, J. D., Remmerswaal, E. B. M., Hordijk, P. L., ten Berge, I. J. M., & van Lier, R. A. W. (2005) · International Immunology · doi:10.1093/intimm/dxh251 · Cited by 36 · cited 1× · see citing works
“In addition, modulation of chemokine receptor expression occurs upon activation, which implies changes in migratory properties of T cell subsets (52,53).”
BackgroundUse of MHC class II tetramers to investigate CD4+ T cell responses: Problems and solutions
Cecconi, V., Moro, M., Mare, S. D., Dellabona, P., & Casorati, G. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20603 · Cited by 35 · cited 1× · see citing works
“(see the articles by Casorati and coworkers (74) or Thiel and coworkers (75), respectively.”
BackgroundFunctional and phenotypic analysis of human memory CD8+ T cells expressing CXCR3
Kobayashi, N., Kondo, T., Takata, H., Yokota, S., & Takiguchi, M. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.1205725 · Cited by 29 · see citing works
FATT‐CTL assay for detection of antigen‐specific cell‐mediated cytotoxicity
van Baalen, C. A., Gruters, R. A., Berkhoff, E. G. M., Osterhaus, A. D. M. E., & Rimmelzwaan, G. F. (2008) · Cytometry Part A · doi:10.1002/cyto.a.20613 · Cited by 18 · cited 3× · see citing works
“For instance, accurate assessment of T cell cytolytic capacity through measurement of perforin production or FATT-CTL assay (see the articles by Betts and coworkers (70) or van Baalen (71), respectively, in the present issue of Cytometry) can only benefit the functional characterization of T cells.”
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A human memory T cell subset with stem cell–like properties
Gattinoni, L., Lugli, E., Ji, Y., Pos, Z., Paulos, C. M., Quigley, M. F., Almeida, J. R., Gostick, E., Yu, Z., Carpenito, C., et al. (2011) · Nature Medicine · doi:10.1038/nm.2446 · Cited by 1,974 · see citing works
Self-citationInflammatory and immune pathways in the pathogenesis of periodontal disease
Cekici, A., Kantarci, A., Hasturk, H., & Van Dyke, T. E. (2014) · Periodontology 2000 · doi:10.1111/prd.12002 · Cited by 1,415 · see citing works
“Receptor Location Cells Bacteria Toll-like receptor 1 Cell membrane Myeloid dendritic cells, monocytes Not specified Toll-like receptor 2 Cell membrane Monocytes, natural killer cells, myeloid dendritic cells,mast cells, T-cells, epithelial cells Porphyromonas gingivalis Escherichia coli Tannerella forsythia Prevotell…”
BackgroundInfluentialAnti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations
Seidel, J. A., Otsuka, A., & Kabashima, K. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00086 · Cited by 1,360 · see citing works
Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis
Brinkmann, V., Billich, A., Baumruker, T., Heining, P., Schmouder, R., Francis, G., Aradhye, S., & Burtin, P. (2010) · Nature Reviews Drug Discovery · doi:10.1038/nrd3248 · Cited by 1,273 · see citing works
PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
Gros, A., Robbins, P. F., Yao, X., Li, Y. F., Turcotte, S., Tran, E., Wunderlich, J. R., Mixon, A., Farid, S., Dudley, M. E., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73639 · Cited by 1,113 · see citing works
“We measured cell surface expression of differentiation markers CD62L, CD45RO, CD27, and CD57 (31), inhibitory receptors PD-1, LAG-3, TIM-3, and BTLA, typically expressed on chronically stimulated CD8 + T cells (23, 24, 32, 33), and costimulatory receptor 4-1BB (28, 34) and IL-2 receptor alpha CD25 (35), which can be u…”
BackgroundInfluentialGuidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
Cossarizza, A., Chang, H., Radbruch, A., Acs, A., Adam, D., Adam‐Klages, S., Agace, W. W., Aghaeepour, N., Akdiş, M., Allez, M., et al. (2019) · European Journal of Immunology · doi:10.1002/eji.201970107 · Cited by 982 · see citing works
The who's who of <scp>T</scp> ‐cell differentiation: Human memory <scp>T</scp> ‐cell subsets
Mahnke, Y. D., Brodie, T. M., Sallusto, F., Roederer, M., & Lugli, E. (2013) · European Journal of Immunology · doi:10.1002/eji.201343751 · Cited by 817 · see citing works
Self-citationSPICE: Exploration and analysis of post‐cytometric complex multivariate datasets
Roederer, M., Nozzi, J. L., & Nason, M. (2011) · Cytometry Part A · doi:10.1002/cyto.a.21015 · Cited by 822 · see citing works
“The complexity of this analysis (and size of the measurement vector) grows geometrically with each additional measurement, such as CD4 vs. CD8, restriction to particular differentiation stages (14), or inclusion of additional functional outcomes.”
BackgroundSelf-citationAn epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease
Horvath, S., Gurven, M., Levine, M. E., Trumble, B. C., Kaplan, H. S., Allayee, H., Ritz, B. R., Chen, B. H., Lu, A. T.-H., Rickabaugh, T. M., et al. (2016) · Genome biology · doi:10.1186/s13059-016-1030-0 · Cited by 729 · see citing works
“Categories of circulating cells were quantified using a predefined population-based gating strategy based on established gating strategies for both T lymphocyte [85] and B lymphocyte [86] subsets.”
MethodGarlet, G. P. (2010) · Journal of Dental Research · doi:10.1177/0022034510376402 · Cited by 724 · see citing works
CD28− T cells: their role in the age-associated decline of immune function
Weng, N., Akbar, A. N., & Goronzy, J. J. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.03.013 · Cited by 629 · see citing works
flowCore: a Bioconductor package for high throughput flow cytometry
Hahne, F., Meur, N. L., Brinkman, R. R., Ellis, B., Haaland, P., Sarkar, D., Špidlen, J., Strain, E. A., & Gentleman, R. C. (2009) · BMC Bioinformatics · doi:10.1186/1471-2105-10-106 · Cited by 586 · see citing works
Reverse Vaccinology: Developing Vaccines in the Era of Genomics
Sette, A., & Rappuoli, R. (2010) · Immunity · doi:10.1016/j.immuni.2010.09.017 · Cited by 561 · see citing works
“However, examining immune responses at the epitope level revealed differences in the quality of the T cell responses associated with different clinical outcomes (Appay et al., 2008; Harari et al., 2006, 2007).”
BackgroundGuidelines for the use of flow cytometry and cell sorting in immunological studies *
Cossarizza, A., Chang, H., Radbruch, A., Akdiş, M., Andrä, I., Annunziato, F., Bächer, P., Barnaba, V., Battistini, L., Bauer, W. M., et al. (2017) · European Journal of Immunology · doi:10.1002/eji.201646632 · Cited by 572 · see citing works
Automated identification of stratifying signatures in cellular subpopulations
Bruggner, R. V., Bodenmiller, B., Dill, D. L., Tibshirani, R. J., & Nolan, G. P. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1408792111 · Cited by 457 · see citing works
“…was also reported by Ganesan et al. and Aghaeepour et al. Of the remaining clusters frequently selected during cross-validation, two (clusters 824715 and 824971) had a phenotype of CCR7 + naive CD4 + T-cells (28), whereas the third (cluster 824823) had a similar phenotype to the Ki-67 + cluster.”
ResultHost response mechanisms in periodontal diseases
Silva, N., Abusleme, L., Bravo, D., Dutzan, N., García-Sesnich, J., Vernal, R., Hernández, M., & Gamonal, J. A. (2015) · Journal of Applied Oral Science · doi:10.1590/1678-775720140259 · Cited by 482 · see citing works
“Toll-like receptor-4 has been shown to specifically recognize lipopolysaccharide of Gram-negative bacteria and acts in cooperation with several protein components, such as lipopolysaccharide-binding protein and CD143,9,112,152. Research has established that toll-like receptors are expressed in periodontal tissues152,2…”
BackgroundMa, C., Fan, R., Ahmad, H., Shi, Q., Comin-Anduix, B., Chodon, T., Koya, R. C., Liu, C.-C., Kwong, G. A., Radu, C. G., et al. (2011) · Nature Medicine · doi:10.1038/nm.2375 · Cited by 441 · see citing works
“Viral infection leads to activated T cells with a large variety of effector functions, as reflected by different cytokine profile”
Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults
Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J., & Davis, M. M. (2013) · Immunity · doi:10.1016/j.immuni.2012.10.021 · Cited by 429 · see citing works
“These memory-phenotype T cells positively correlate with T cell frequency (Figure 3D) and have similar frequencies of central memory-phenotype cells by chemokine receptor CCR7 expression as influenza-specific T cells (Appay et al., 2008) (Figure S3).”
BackgroundMethodThe Alarmin Interleukin-33 Drives Protective Antiviral CD8 + T Cell Responses
Bonilla, W. V., Fröhlich, A., Senn, K., Kallert, S. M., Fernandez, M., Johnson, S., Kreutzfeldt, M., Hegazy, A. N., Schrick, C., Fallon, P. G., et al. (2012) · Science · doi:10.1126/science.1215418 · Cited by 417 · see citing works
Tailoring Materials for Modulation of Macrophage Fate
Li, J., Jiang, X., Li, H., Gelinsky, M., & Gu, Z. (2021) · Advanced Materials · doi:10.1002/adma.202004172 · Cited by 402 · see citing works
p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells
Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75051 · Cited by 389 · see citing works
Bengsch, B., Seigel, B., Ruhl, M., Timm, J., Kuntz, M., Blum, H. E., Pircher, H., & Thimme, R. (2010) · PLoS Pathogens · doi:10.1371/journal.ppat.1000947 · Cited by 373 · see citing works
“[18] and extends previous reports regarding the differentiation of HCV-specific CD8+ T cells that used conventional 4-color flow cytometry [18,28].”
BackgroundResultPark, L. M., Lannigan, J., & Jaimes, M. C. (2020) · Cytometry Part A · doi:10.1002/cyto.a.24213 · Cited by 350 · see citing works
“The addition of CD27 and CD28 allows further refinement of those subsets, identifying early effector (CD45RA−CCR7−CD28+CD27+), early-like effector (CD45RA−CCR7−CD28+CD27−), intermediate effector (CD45RA−CCR7−CD28−CD27+), terminal effector (CD45RA−CCR7−CD28−CD27−), and RA-terminal effector (CD45RA+CCR7−CD28−CD27−) (42,…”
BackgroundSingle-cell technologies for monitoring immune systems
Chattopadhyay, P. K., Gierahn, T. M., Roederer, M., & Love, J. C. (2014) · Nature Immunology · doi:10.1038/ni.2796 · Cited by 368 · see citing works
Self-citationFrom “truly naïve” to “exhausted senescent” T cells: When markers predict functionality
Larbi, A., & Fulop, T. (2014) · Cytometry Part A · doi:10.1002/cyto.a.22351 · Cited by 359 · see citing works
Epidemiology and Immune Pathogenesis of Viral Sepsis
Lin, G.-L., McGinley, J. P., Drysdale, S. B., & Pollard, A. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02147 · Cited by 351 · see citing works
“Less pronounced immune exhaustion was produced in mouse CD8 cells by infection with Epstein-Barr virus (EBV), measles virus, and CMV (222) (223) (224) (225) .”
BackgroundHegazy, A. N., West, N. R., Stubbington, M. J. T., Wendt, E., Suijker, K. I. M., Datsi, A., This, S., Danne, C., Campion, S., Duncan, S. H., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.07.047 · Cited by 338 · see citing works
The Yellow Fever Virus Vaccine Induces a Broad and Polyfunctional Human Memory CD8+ T Cell Response
Akondy, R. S., Monson, N. D., Miller, J. D., Edupuganti, S., Teuwen, D. E., Wu, H. G., Quyyumi, F. F., Garg, S., Altman, J. D., del Rı́o, C., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803903 · Cited by 345 · see citing works
“Coexpression of CCR7, a homing marker, and CD45RA, a transmembrane tyrosine phosphatase, is characteristic of naive cells (36).”
Polyfunctional responses by human T cells result from sequential release of cytokines
Han, Q., Bagheri, N., Bradshaw, E. M., Hafler, D. A., Lauffenburger, D. A., & Love, J. C. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1117194109 · Cited by 329 · see citing works
T cell exhaustion during persistent viral infections
Kahan, S. M., Wherry, E. J., & Zajac, A. J. (2015) · Virology · doi:10.1016/j.virol.2014.12.033 · Cited by 321 · see citing works
“Infections such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV) that persist but do not result in such marked and prolonged antigenic activation are associated with intermediate T cell phenotypes (Appay et al., 2008, 2002; Tussey et al., 2003).”
BackgroundHadrup, S. R., Bakker, A. H., Shu, C. J., Andersen, R. S., van Veluw, J., Hombrink, P., Castermans, E., thor Straten, P., Blank, C., Haanen, J. B., et al. (2009) · Nature Methods · doi:10.1038/nmeth.1345 · Cited by 306 · see citing works
Li, W., Lu, L., Lu, J., Wang, X., Yang, C., Jin, J., Wu, L., Hong, X., Li, F., Cao, D., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay9013 · Cited by 305 · see citing works
Periodontal Disease: Linking the Primary Inflammation to Bone Loss
Benedetto, A. D., Gigante, I., Colucci, S. C., & Grano, M. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/503754 · Cited by 300 · see citing works
“Activated CD4 T-helper cells produce subsets of cytokines which will define phenotypically distinguished immune responses:Th-1 andTh-2 cells, respectively, associate with cellular and humoral immunity [29] and the recently described Th-17 and T regulatory (Treg) cells, which have antagonistic roles as effector and sup…”
Illingworth, J. J., Butler, N. S., Roetynck, S., Mwacharo, J., Pierce, S. K., Bejon, P., Crompton, P. D., Marsh, K., & Ndungu, F. M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202438 · Cited by 290 · see citing works
“CD45RA reexpressing T cells have a highly differentiated effector-like phenotype (51, 53).”
Exercise and the aging immune system
Simpson, R. J., Lowder, T. W., Spielmann, G., Bigley, A. B., LaVoy, E. C., & Kunz, H. (2012) · Ageing Research Reviews · doi:10.1016/j.arr.2012.03.003 · Cited by 281 · see citing works
Evidence of premature immune aging in patients thymectomized during early childhood
Sauce, D., Larsen, M., Fastenackels, S., Duperrier, A., Keller, M., Grubeck-Loebenstein, B., Ferrand, C., Debré, P., Sidi, D., & Appay, V. (2009) · Journal of Clinical Investigation · doi:10.1172/jci39269 · Cited by 278 · see citing works
Self-citationBengsch, B., Martin, B., & Thimme, R. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.07.005 · Cited by 284 · see citing works
“Flu-specific CD8+ T cells) [26].”
MethodHenson, S. M., Franzese, O., Macaulay, R., Libri, V., Azevedo, R. I., Kiani-Alikhan, S., Plunkett, F. J., Masters, J. E., Jackson, S., Griffiths, S. J., et al. (2009) · Blood · doi:10.1182/blood-2009-01-199588 · Cited by 262 · see citing works
Functional Signatures of Human CD4 and CD8 T Cell Responses to Mycobacterium tuberculosis
Prezzemolo, T., Guggino, G., Manna, M. P. L., Liberto, D. D., Dieli, F., & Caccamo, N. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00180 · Cited by 268 · see citing works
Inhibitory Receptors Beyond T Cell Exhaustion
Marraco, S. A. F., Neubert, N. J., Verdeil, G., & Speiser, D. E. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00310 · Cited by 242 · see citing works
Duraiswamy, J., Ibegbu, C., Masopust, D., Miller, J. D., Araki, K., Doho, G., Tata, P., Sk, G., Zilliox, M. J., Nakaya, H. I., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1001783 · Cited by 246 · see citing works
Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells
Di Mitri, D., Azevedo, R. I., Henson, S. M., Libri, V., Riddell, N. E., Macaulay, R., Kipling, D., Soares, M. V. D., Battistini, L., & Akbar, A. N. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100978 · Cited by 231 · see citing works
“CD45RACD27(2) T cells are mainly CD27(2) CD28(2) in both CD4 and CD8 subpopulations but not all CD27(2) CD28(2) T cells express CD45RA (4).”
BackgroundMethodInfluentialMartínez‐Zamudio, R. I., Dewald, H. K., Vasilopoulos, T., Gittens‐Williams, L., Fitzgerald‐Bocarsly, P., & Herbig, U. (2021) · Aging Cell · doi:10.1111/acel.13344 · Cited by 213 · see citing works
“…with advancing age, irrespective of their differentiation state CD8+ T- cell populations can be divided into distinct subsets based on their functions, and the expression of cell surface receptors CCR7 and CD45RA, among others (Appay et al., 2008; Farber et al., 2014; Sallusto et al., 1999).”
BackgroundInfection and inflammatory mechanisms
Dyke, T. E. V., & Winkelhoff, A. J. V. (2013) · Journal of Periodontology · doi:10.1902/jop.2013.1340018 · Cited by 221 · see citing works
Fuertes Marraco, S. A., Soneson, C., Cagnon, L., Gannon, P. O., Allard, M., Maillard, S. A., Montandon, N., Rufer, N., Waldvogel, S., Delorenzi, M., et al. (2015) · Science Translational Medicine · doi:10.1126/scitranslmed.aaa3700 · Cited by 206 · see citing works
When aging reaches CD4+ T-cells: phenotypic and functional changes
Moro‐García, M. A. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00107 · Cited by 212 · see citing works
“…of CD28 molecule, expression of NK cell-related receptors www.frontiersin.org May 2013 | Volume 4 | Article 107 | 3 (NKRs), production of molecules involved in cellular cytotoxicity (perforin and granzyme), and a substantial increase in the production of IFN-γ (Appay et al., 2008) (Table 1).”
BackgroundInfluentialPremature aging of circulating T cells in patients with end-stage renal disease
Betjes, M. G. H., Langerak, A. W., van der Spek, A., de Wit, E. A., & Litjens, N. H. R. (2011) · Kidney International · doi:10.1038/ki.2011.110 · Cited by 207 · see citing works
The Effects of TLR Activation on T-Cell Development and Differentiation
Jin, B., Sun, T., Yu, X., Yang, Y., & Yeo, A. E. T. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/836485 · Cited by 202 · see citing works
“T cells are divided into different subsets based on their phenotypes, intracellular molecules expression, cytokine production, the lengths of telomeres and state of immunity [17].”
BackgroundHla, T., & Brinkmann, V. (2011) · Neurology · doi:10.1212/wnl.0b013e31820d5ec1 · Cited by 201 · see citing works
Ma, C. S., Wong, N. S. M., Rao, G., Avery, D. T., Torpy, J., Hambridge, T., Bustamante, J. C., Okada, S., Stoddard, J. L., Deenick, E. K., et al. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2015.05.036 · Cited by 199 · see citing works
Luabeya, A. K. K., Kagina, B. M. N., Tameris, M. D., Geldenhuys, H. D., Hoff, S. T., Shi, Z., Kromann, I., Hatherill, M., Mahomed, H., Hanekom, W. A., et al. (2015) · Vaccine · doi:10.1016/j.vaccine.2015.06.051 · Cited by 194 · see citing works
Yamamoto, T., Price, D. A., Casazza, J. P., Ferrari, G., Nason, M., Chattopadhyay, P. K., Roederer, M., Emma Gostick, D., Katsikis, P. D., Douek, D. C., et al. (2011) · Blood · doi:10.1182/blood-2010-11-317297 · Cited by 191 · see citing works
Self-citationDOCK8 deficiency impairs CD8 T cell survival and function in humans and mice
Randall, K. L., Chan, S. S.-Y., Ma, C. S., Fung, I. T. H., Mei, Y., Yabas, M., Tan, A. H., Arkwright, P. D., Alsuwairi, W., Reyes, S. O. L., et al. (2011) · The Journal of Experimental Medicine · doi:10.1084/jem.20110345 · Cited by 186 · see citing works
“A feature of the TEMRA cell population is expression of CD57 on a substantial proportion of these cells (Appay et al., 2008).”
BackgroundInfluentialAndrogen receptor-mediated CD8+ T cell stemness programs drive sex differences in antitumor immunity
Yang, C., Jin, J., Yang, Y., Sun, H., Wu, L., Shen, M., Hong, X., Li, W., Lu, L., Cao, D., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.05.012 · Cited by 191 · see citing works
The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity
Gautam, S., Fioravanti, J., Zhu, W., Gall, J. B. L., Brohawn, P. Z., Lacey, N. E., Hu, J., Hocker, J. D., Hawk, N. V., Kapoor, V., et al. (2019) · Nature Immunology · doi:10.1038/s41590-018-0311-z · Cited by 180 · see citing works
Properties of end-stage human T cells defined by CD45RA re-expression
Henson, S. M., Riddell, N. E., & Akbar, A. N. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.04.001 · Cited by 180 · see citing works
“T cell differentiation can be defined using the relative levels of expression of CD27, CD28 and CD45RA [17,21,30,31], with highly differentiated end-stage T cells being CD45RACD27 CD28 .”
BackgroundInfluentialAntiviral and Regulatory T Cell Immunity in a Patient with Stromal Interaction Molecule 1 Deficiency
Fuchs, S. P., Rensing‐Ehl, A., Speckmann, C., Bengsch, B., Schmitt-Graeff, A. H., Bondzio, I., Maul‐Pavicic, A., Bass, T., Vraetz, T., Strahm, B., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1102507 · Cited by 179 · see citing works
“The differentiation state of CD8 T cells was analyzed using the markers CD27, CCR7, and CD45RA, which allow classification of CD8 T cells from naive to terminally differentiated CTL into five subgroups (20).”
MethodRegulatory T cells attenuate experimental periodontitis progression in mice
Garlet, G. P., Cardoso, C. R. D. B., Mariano, F. S., Claudino, M., de Assis, G. F., Campanelli, A. P., Ávila-Campos, M. J., & Silva, J. S. (2010) · Journal Of Clinical Periodontology · doi:10.1111/j.1600-051x.2010.01586.x · Cited by 177 · see citing works
Mitochondrial mass governs the extent of human T cell senescence
Callender, L. A., Carroll, E. C., Bober, E., Akbar, A. N., Solito, E., & Henson, S. M. (2019) · Aging Cell · doi:10.1111/acel.13067 · Cited by 167 · see citing works
Pallikkuth, S., Parmigiani, A., Silva, S. Y., George, V. K., Fischl, M. A., Pahwa, R., & Pahwa, S. G. (2012) · Blood · doi:10.1182/blood-2011-12-396648 · Cited by 162 · see citing works
Contribution of Naïve and Memory T-Cell Populations to the Human Alloimmune Response
Macedo, C., Orkis, E. A., Popescu, I., Elinoff, B. D., Zeevi, A., Shapiro, R., Lakkis, F. G., & Metes, D. (2009) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2009.02742.x · Cited by 161 · see citing works
“We therefore purified CD3+ cells from leukapheresis products of nine healthy subjects and separated them into TN, TCM, TEM and TEMRA (24,25).”
BackgroundMethodInfluentialHuman RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections
Crequer, A., Troeger, A., Patin, E., Ma, C. S., Picard, C., Pedergnana, V., Fieschi, C., Lim, A., Abhyankar, A., Gineau, L., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci62949 · Cited by 159 · see citing works
“This exhaustion phenotype and the expansion of memory T cell subsets were previously observed in other cases of chronic infection, including for patients with PIDs (32, 33), suggesting that the increase of memory T cells and their exhaustion phenotype are more likely to be consequences of chronic infection rather than…”
Lymphocytes in obesity-related adipose tissue inflammation
Chatzigeorgiou, A., Karalis, K. P., Bornstein, S. R., & Chavakis, T. (2012) · Diabetologia · doi:10.1007/s00125-012-2607-0 · Cited by 157 · see citing works
Infection and inflammatory mechanisms
Dyke, T. E. V., & Winkelhoff, A. J. V. (2013) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12088 · Cited by 154 · see citing works
Henson, S. M., Macaulay, R., Riddell, N. E., Nunn, C. J., & Akbar, A. N. (2015) · European Journal of Immunology · doi:10.1002/eji.201445312 · Cited by 146 · see citing works
T-Cell Immunity to Infection with Dengue Virus in Humans
Weiskopf, D., & Sette, A. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00093 · Cited by 150 · see citing works
Chiang, S. C. C., Theorell, J., Entesarian, M., Meeths, M., Mastafa, M., Al–Herz, W., Frisk, P., Gilmour, K. C., Ifversen, M., Langenskiöld, C., et al. (2013) · Blood · doi:10.1182/blood-2012-07-442558 · Cited by 147 · see citing works
Alarmin IL-33 Acts as an Immunoadjuvant to Enhance Antigen-Specific Tumor Immunity
Villarreal, D. O., Wise, M. C., Walters, J. N., Reuschel, E. L., Choi, M. J., Obeng-Adjei, N., Yan, J., Morrow, M. P., & Weiner, D. B. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-2729 · Cited by 147 · see citing works
Iannello, A., Boulassel, M., Samarani, S., Débbeche, O., Tremblay, C. L., Toma, E., Routy, J., & Ahmad, A. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0901967 · Cited by 144 · see citing works
“It is noteworthy that the CD272CD45RA2CCR72 subset of CD4+ T cells is fully differentiated and produces maximum quantities of IFN-g (40).”
MethodInfluentialMa, C., Cheung, A. F., Chodon, T., Koya, R. C., Wu, Z., Ng, C., Avramis, E. V., Cochran, A. J., Witte, O. N., Baltimore, D., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0383 · Cited by 144 · see citing works
“Naïve cells were classified as CD45+/CCR7+/CCR5−/PD1−, CD27+/ CD28−/CD62L+, and CD45+/CCR7+/CCR5−/PD1+; central memory as CD45RO−/ CD25−/HLA-DR−/CD127+; effector memory as CD45−/ CCR7−/CCR5+/PD1+, CD45−/ CCR7−/CCR5−/PD1+, CD45−/CCR7−/ CCR5−/PD1−, CD45−/CCR7−/CCR5−/PD1−, and CD27−/CD28−/ CD62L−; effector memory RA (EMR…”
Pillet, S., Aubin, É., Trépanier, S., Bussière, D., Dargis, M., Poulin, J., Yassine‐Diab, B., Ward, B. J., & Landry, N. (2016) · Clinical Immunology · doi:10.1016/j.clim.2016.03.008 · Cited by 143 · see citing works
Specific expression of GPR56 by human cytotoxic lymphocytes
Peng, Y.-M., van de Garde, M. D. B., Cheng, K.-F., Baars, P. A., Remmerswaal, E. B. M., van Lier, R. A. W., Mackay, C. R., Lin, H., & Hamann, J. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.0211092 · Cited by 142 · see citing works
“CD8 T cells can be subdivided, based on the expression of CD27 and CD45RA, into naive, memory-type, and effector-type cells [14], Although CD27 CD45RA effector-type cells strongly expressed GPR56, staining was very weak on memory cells and absent on naive cells (Fig.”
BackgroundPachnio, A., Ciaúrriz, M., Begum, J., Lal, N., Zuo, J., Beggs, A. D., & Moss, P. A. H. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005832 · Cited by 141 · see citing works
Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence.
Dock, J., & Effros, R. B. (2011) · Europe PMC (PubMed Central) · Cited by 137 · see citing works
Saba, E., Grivel, J., Vanpouille, C., Břicháček, B., Fitzgerald, W., Margolis, L. B., & Lisco, A. (2010) · Mucosal Immunology · doi:10.1038/mi.2010.2 · Cited by 138 · see citing works
More tricks with tetramers: a practical guide to staining T cells with peptide– MHC multimers
Dolton, G. M., Tungatt, K., Lloyd, A., Bianchi, V., Theaker, S. M., Trimby, A., Holland, C. J., Donia, M., Godkin, A. J., Cole, D. K., et al. (2015) · Immunology · doi:10.1111/imm.12499 · Cited by 137 · see citing works
Oja, A. E., Piet, B., van der Zwan, D., Blaauwgeers, H., Mensink, M., de Kivit, S., Borst, J., Nolte, M. A., van Lier, R. A. W., Stark, R., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02654 · Cited by 130 · see citing works
Laanani, M., Ghosn, J., Essat, A., Mélard, A., Seng, R., Gousset, M., Panjo, H., Mortier, E., Girard, P., Goujard, C., et al. (2015) · Clinical Infectious Diseases · doi:10.1093/cid/civ171 · Cited by 130 · see citing works
“This could be explained notably because of the higher level of immune activation and expression of CCR5 coreceptors on transitional and effector memory T cells than on naive and central memory cells [31, 32].”
Luque‐Campos, N., Contreras-López, R. A., Paredes-Martínez, M. J., Torres, M. J., Bahraoui, S., Wei, M., Espinoza, F., Djouad, F., Elizondo-Vega, R. J., & Luz‐Crawford, P. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00798 · Cited by 128 · see citing works
Fergusson, J. R., Hühn, M. H., Swadling, L., Walker, L. J., Kurioka, A., Llibre, A., Bertoletti, A., Holländer, G. A., Newell, E. W., Davis, M. M., et al. (2015) · Mucosal Immunology · doi:10.1038/mi.2015.69 · Cited by 125 · see citing works
The Crossroads of the Coagulation System and the Immune System: Interactions and Connections
Wilhelm, G., Mertowska, P., Mertowski, S., Przysucha, A., Strużyna, J., Grywalska, E., & Torres, K. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241612563 · Cited by 132 · see citing works
Phenotypic maturation of porcine NK- and T-cell subsets
Talker, S. C., Käser, T., Reutner, K., Sedlak, C., Mair, K. H., Koinig, H. C., Graage, R., Viehmann, M., Klingler, E., Ladinig, A., et al. (2013) · Developmental & Comparative Immunology · doi:10.1016/j.dci.2013.01.003 · Cited by 127 · see citing works
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 · see citing works
T-cells in chronic lymphocytic leukemia: Guardians or drivers of disease?
Roessner, P. M., & Seiffert, M. (2020) · Leukemia · doi:10.1038/s41375-020-0873-2 · Cited by 128 · see citing works
β-Cell–Specific CD8 T Cell Phenotype in Type 1 Diabetes Reflects Chronic Autoantigen Exposure
Skowera, A., Ladell, K., McLaren, J. E., Dolton, G. M., Matthews, K. K., Emma Gostick, D., Kronenberg‐Versteeg, D., Eichmann, M., Knight, R. R., Heck, S., et al. (2014) · Diabetes · doi:10.2337/db14-0332 · Cited by 118 · see citing works
“These markers classically delineate naïve and early memory T cells (30; 31).”
BackgroundLibri, V., Azevedo, R. I., Jackson, S. E., Di Mitri, D., Lachmann, R., Fuhrmann, S., Vukmanovic-Stejic, M., Yong, K., Battistini, L., Kern, F., et al. (2011) · Immunology · doi:10.1111/j.1365-2567.2010.03386.x · Cited by 111 · see citing works
How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?
Ananworanich, J., Dubé, K., & Chomont, N. (2014) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000122 · Cited by 118 · see citing works
“The pathway of T cell differentiation, that is, the sequence of development of the different T-cell subsets, remains elusive in humans, and it is unclear if the differentiation pathway is linear or branched, one-way or reversible [31].”
Human circulating and tissue-resident memory CD8+ T cells
Buggert, M., Price, D. A., Mackay, L. K., & Betts, M. R. (2023) · Nature Immunology · doi:10.1038/s41590-023-01538-6 · Cited by 119 · see citing works
Wieten, R. W., Jonker, E. F. F., van Leeuwen, E. M. M., Remmerswaal, E. B. M., ten Berge, I. J. M., de Visser, A. W., van Genderen, P. J. J., Goorhuis, A., Visser, L. G., Grobusch, M. P., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149871 · Cited by 114 · see citing works
Is immunosenescence influenced by our lifetime “dose” of exercise?
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The 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 110 · see citing works
Impact of age on T cell signaling: A general defect or specific alterations?
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Stelma, F., Niet, A. D., Sinnige, M. J., van Dort, K. A., van Gisbergen, K. P. J. M., Verheij, J., van Leeuwen, E. M. M., Kootstra, N. A., & Reesink, H. W. (2017) · Scientific Reports · doi:10.1038/s41598-017-06352-3 · Cited by 106 · see citing works
Broadley, I., Pera, A., Morrow, G., Davies, K. A., & Kern, F. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00195 · Cited by 103 · see citing works
Stemberger, C., Graef, P., Odendahl, M., Albrecht, J., Dössinger, G., Anderl, F., Buchholz, V. R., Gasteiger, G., Schiemann, M., Grigoleit, G. U., et al. (2014) · Blood · doi:10.1182/blood-2013-12-547349 · Cited by 106 · see citing works
Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients
Meijers, R. W. J., Litjens, N. H. R., de Wit, E. A., Langerak, A. W., van der Spek, A., Baan, C. C., Weimar, W., & Betjes, M. G. H. (2012) · Immunity & Ageing · doi:10.1186/1742-4933-9-19 · Cited by 106 · see citing works
“; licensee BioMed Central Commons Attribution License (http://creativec reproduction in any medium, provided the or CCR7, able to home into lymphoid tissues), effector memory (EM, CD45ROCCR7, exerting direct effector functions) and the more terminally differentiated effector memory CD45RA (EMRA, CD45ROCCR7, high in ef…”
BackgroundCD40L expression permits CD8+ T cells to execute immunologic helper functions
Frentsch, M., Stark, R., Matzmohr, N., Meier, S., Durlanik, S., Schulz, A. R., Stervbo, U., Jürchott, K., Gebhardt, F., Heine, G., et al. (2013) · Blood · doi:10.1182/blood-2013-02-483586 · Cited by 100 · see citing works
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“However, whether the early-differentiated CD8+ T cells (CD27+ CD28+) that decreased in the more severe clinical picture will increase after trypanocidal treatment and whether this T cell subset can be used as a surrogate marker for treatment success remain to be explored.”
BackgroundInfluentialCurriu, M., Carrillo, J., Massanella, M., Rigau, J., Alegre, J., Puig, J., Garcia-Quintana, A. M., Castro‐Marrero, J., Negredo, E., Clotet, B., et al. (2013) · Journal of Translational Medicine · doi:10.1186/1479-5876-11-68 · Cited by 105 · see citing works
“Figure 2C shows that in our study, the percentage of CD57 expressing NK cells is similar among groups, although the intensity of CD57 staining showed significantly lower values in CFS individuals.”
BackgroundResultInfluentialThe Role of Natural Killer Cells and CD8+ T Cells in Hepatitis B Virus Infection
Schuch, A., Hoh, A., & Thimme, R. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00258 · Cited by 105 · see citing works
- Authors
- Appay, V., van Lier, R. A. W., Sallusto, F., & Roederer, M.
- Affiliations
- Inserm (FR)
- Institute for Research in Biomedicine (CH)
- National Institutes of Health (US)
- Corresponding author
- Appay, Victor
- Venue
- Cytometry Part A
- Publisher
- Wiley
- Published
- 2008-10-22
- Volume
- 73A
- Issue
- 11
- Pages
- 975-983
- ISSN
- 1552-4922 (ISSN-L)
- 1552-4930
- OpenAlex
- W1574493485
- Cited by
- 729
- References
- 76
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 21 · 2023: 24 · 2022: 19 · 2021: 38 · 2020: 45 · 2019: 46 · 2018: 42 · 2017: 47 · 2016: 52 · 2015: 60 · 2014: 51 · 2013: 69 · 2012: 53
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- Cytometry Part A (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- 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 › Virology › HIV Research and Treatment
- Keywords
- T cell subsets, T cell differentiation, T cell heterogeneity, T cell phenotype, T cell function, immune response, infection
- MeSH terms
- Humans, Inflammation, Lymphocyte Activation, Phenotype, T-Lymphocyte Subsets, Consensus
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