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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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“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
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“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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“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,…”
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Periodontal Disease: Linking the Primary Inflammation to Bone Loss
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Exercise and the aging immune system
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BackgroundInfection and inflammatory mechanisms
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BackgroundInfluentialPremature aging of circulating T cells in patients with end-stage renal disease
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“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].”
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Self-citationDOCK8 deficiency impairs CD8 T cell survival and function in humans and mice
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“A feature of the TEMRA cell population is expression of CD57 on a substantial proportion of these cells (Appay et al., 2008).”
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Properties of end-stage human T cells defined by CD45RA re-expression
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“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
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“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 175
Mitochondrial mass governs the extent of human T cell senescence
Callender, L. A., Carroll, E. C., Bober, E. A., Akbar, A. N., Solito, E., & Henson, S. M. (2019) · Aging Cell · doi:10.1111/acel.13067 · Cited by 172
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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
“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
“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 163
Infection and inflammatory mechanisms
Dyke, T. E. V., & Winkelhoff, A. J. V. (2013) · Journal Of Clinical Periodontology · doi:10.1111/jcpe.12088 · Cited by 153
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
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
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 150
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
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 147
“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 145
“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 146
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 141
“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 145
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
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
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
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
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
“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 132
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 130
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 138
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
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
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 131
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
“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
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 127
“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 125
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 119
Is immunosenescence influenced by our lifetime “dose” of exercise?
Turner, J. E. (2016) · Biogerontology · doi:10.1007/s10522-016-9642-z · Cited by 112
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 113
Impact of age on T cell signaling: A general defect or specific alterations?
Larbi, A., Pawelec, G., Wong, S. C., Goldeck, D., Tai, J. J.-Y., & Fulop, T. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.09.008 · Cited by 108
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 110
Broadley, I., Pera, A., Morrow, G., Davies, K. A., & Kern, F. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00195 · Cited by 103
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
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
“; 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
Pinazo, M., Thomas, M. C., Bustamante, J. M., de Almeida, I. C., López, M. C., & Gascón, J. (2015) · Memórias do Instituto Oswaldo Cruz · doi:10.1590/0074-02760140435 · Cited by 105
“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 108
“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 111
Metadata
- 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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