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Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells
Open accessAbstract
Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.
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“In terms of surface phenotype, the best accepted combination of markers is high expression of the IL-2 receptor α chain (CD25) and low expression of the IL-7R α chain (CD127) [134, 385].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [385]
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BackgroundInterleukin-2 signaling in the regulation of T cell biology in autoimmunity and cancer
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“Some studies have proposed that almost all human FoxP3 + T cells can be identified as expressing low levels of the IL-7α receptor (CD127) and that detection of low levels of CD127 can be useful for isolating human T REGs”
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Gregori, S., Goudy, K., & Roncarolo, M. G. (2012) · Frontiers in Immunology · doi:10.3389/fimmu.2012.00030 · Cited by 173
“…occurring FOXP3+ Treg are identified and distinguished from activated CD4+ T cells by the expression of low levels of CD127 (Liu et al., 2006; Seddiki et al., 2006), and of CD49d (Kleinewietfeld et al., 2009), and by the DNA demethylation of a specific region of the FOXP3 gene called…”
BackgroundCD molecules 2006 — Human cell differentiation molecules
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“While Yamagiwa et al. (2001) reported that TGF-b promotes endogenous CD4+CD25+ cells, our group first reported that TGF-b does have an ability to induce CD4+CD252 cells to become CD4+CD25+ Tregs in vitro (Zheng et al.”
BackgroundMethodEbinuma, H., Nakamoto, N., Li, Y., Price, D. A., Emma Gostick, D., Levine, B. L., Tobias, J. W., Kwok, W. W., & Chang, K. (2008) · Journal of Virology · doi:10.1128/jvi.01548-07 · Cited by 160
“cells in HCV-infected and uninfected subjects were mostly negative for CD127 (IL-7 receptor ), as reported for natural Tregs (32, 50).”
BackgroundHuman regulatory T cells and autoimmunity
Costantino, C. M., Baecher‐Allan, C., & Hafler, D. A. (2008) · European Journal of Immunology · doi:10.1002/eji.200738104 · Cited by 158
“CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells.”
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InfluentialThe Environment of Regulatory T Cell Biology: Cytokines, Metabolites, and the Microbiome
Hoeppli, R. E., Wu, D., Cook, L., & Levings, M. K. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00061 · Cited by 162
“Recent work by Lu et al. has demonstrated that pre-treatment of human CD4+CD25highCD127low Tregs with ATRA almost completely prevents IL-1β/IL-6-driven conversion to Th1/Th17-like cells (128).”
BackgroundInfluentialMcGary, C. S., Deléage, C., Harper, J. L., Micci, L., Ribeiro, S. P., Paganini, S., Kuri-Cervantes, L., Benne, C., Ryan, E. S., BALDERAS, R. S., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.09.018 · Cited by 162
“…in CD25+ CD127lo cells which also expressed Forkhead Box P3 (FoxP3), the master transcription factor of Treg cells, when compared to bulk memory CD4+ T cells as well as PD-1+CTLA-4 , PD1+CTLA-4+, and PD-1 CTLA-4 memory CD4+ T cell subsets (Figure 2B; Anderson et al., 2008; Seddiki et al., 2006).”
BackgroundCurrent approaches in dendritic cell generation and future implications for cancer immunotherapy
Tuyaerts, S., Aerts, J. L., Corthals, J., Neyns, B., Heirman, C., Breckpot, K., Thielemans, K., & Bonehill, A. (2007) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-007-0334-z · Cited by 156
Moradi, B., Schnatzer, P., Hagmann, S., Rosshirt, N., Gotterbarm, T., Kretzer, J. P., Thomsen, M. N., Lorenz, H., Zeifang, F., & Tretter, T. (2014) · Arthritis Research & Therapy · doi:10.1186/ar4545 · Cited by 155
“Kim CH: Migration and function of FoxP3+ regulatory T cells in the hematolymphoid system.”
BackgroundResultInfluentialMinigo, G., Woodberry, T., Piera, K. A., Salwati, E., Tjitra, E., Kenangalem, E., Price, R. N., Engwerda, C. R., Anstey, N. M., & Plebanski, M. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000402 · Cited by 154
“Natural Treg cells characterized by the expression of the transcription factor forkhead box P3 (Foxp3) [1,2], the IL-2 receptor a chain CD25 [3] and low expression levels of the IL-7 receptor a (CD127) [4,5], are widely accepted to be a specialized immunosuppressive subpopulation of CD4+ T cells [2].”
BackgroundInfluentialSmith, M. E., Tourigny, M. R., Noakes, P. S., Thornton, C. A., Tulić, M. K., & Prescott, S. L. (2008) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2008.03.025 · Cited by 149
Subsets of regulatory T cells and their roles in allergy
Zhang, H., Kong, H., Zeng, X., Guo, L., Sun, X., & He, S. (2014) · Journal of Translational Medicine · doi:10.1186/1479-5876-12-125 · Cited by 149
“It has also been reported inverse correlation between expression of FoxP3 and CD127 in CD4 + CD25+ T cells, which suggests that cell surface expression of CD127 can be used as a flexible alternative to the transcription factor FoxP3 for identifying and isolating human Tregs for functional analysis [14].”
BackgroundHäringer, B., Lozza, L., Steckel, B., & Geginat, J. (2009) · Journal of Experimental Medicine · doi:10.1084/jem.20082238 · Cited by 150
Ronchetti, S., Ricci, E., Petrillo, M. G., Cari, L., Migliorati, G., Nocentini, G., & Riccardi, C. (2015) · Journal of Immunology Research · doi:10.1155/2015/171520 · Cited by 152
Suppression assays with human T regulatory cells: A technical guide
McMurchy, A. N., & Levings, M. K. (2012) · European Journal of Immunology · doi:10.1002/eji.201141651 · Cited by 147
IL-7 in human health and disease
Lundström, W., Fewkes, N. M., & Mackall, C. L. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.02.005 · Cited by 158
CTL quality and the control of human retroviral infections
Bangham, C. R. M. (2009) · European Journal of Immunology · doi:10.1002/eji.200939451 · Cited by 149
A Function for IL-7R for CD4+CD25+Foxp3+ T Regulatory Cells
Bayer, A. L., Lee, J. Y., de la Barrera, A., Surh, C. D., & Malek, T. R. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.1.225 · Cited by 157
“The present finding also confirms previously published reports on mouse Treg cells and is in line with the phenotype of human Treg cells in the peripheral blood of both healthy and type 1 diabetic patients (26, 27).”
ResultDisturbed regulatory T cell homeostasis in multiple sclerosis
Venken, K., Hellings, N., Liblau, R., & Stinissen, P. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.12.003 · Cited by 150
Natural Regulatory T Cells and Persistent Viral Infection
Li, S., Gowans, E. J., Chougnet, C. A., Plebanski, M., & Dittmer, U. (2007) · Journal of Virology · doi:10.1128/jvi.01768-07 · Cited by 154
“It was recently reported that surface expression of CD127 (the IL-7 receptor) was high on effector T cells and low on Treg and allows reliable and convenient recognition of Treg (CD25 CD127 ) from effector cells (CD25 CD127 ) (55, 85, 113).”
BackgroundMjösberg, J., Svensson‐Arvelund, J., Johansson, E., Hellström, L., Casas, R., Jenmalm, M. C., Boij, R., Matthiesen, L., Jönsson, J., Berg, G. E., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0803654 · Cited by 148
“gene for Foxp3 that correlates with suppressive function (9, 10).”
BackgroundImbalance of Circulating Th17 and Regulatory T Cells in Alzheimer’s Disease: A Case Control Study
Oberstein, T. J., Taha, L., Spitzer, P., Hellstern, J., i, M. H., Kornhuber, J., & Maler, J. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01213 · Cited by 153
Functional reprogramming of regulatory T cells in the absence of Foxp3
Charbonnier, L.-M., Cui, Y., Stephen-Victor, E., Harb, H., Lopez, D., Bleesing, J. J., Garcia-Lloret, M. I., Chen, K., Ozen, A., Carmeliet, P., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0442-x · Cited by 145
Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly
Veerapathran, A., Pidala, J., Beato, F., Yu, X., & Anasetti, C. (2011) · Blood · doi:10.1182/blood-2011-02-337097 · Cited by 144
Induction of regulatory T cells: A role for probiotics and prebiotics to suppress autoimmunity
Dwivedi, M., Kumar, P., Laddha, N. C., & Kemp, E. H. (2016) · Autoimmunity Reviews · doi:10.1016/j.autrev.2016.01.002 · Cited by 145
Steinborn, A., Schmitt, E., Kisielewicz, A., Rechenberg, S., Seissler, N., Mahnke, K., Schaier, M., Zeier, M. G., & Sohn, C. (2011) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2011.04493.x · Cited by 142
Magenau, J. M., Qin, X., Tawara, I., Rogers, C. E., Kitko, C. L., Schlough, M., Bickley, D., Braun, T., Jang, P., Lowler, K. P., et al. (2010) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2010.02.026 · Cited by 143
Differential Regulation of the Let-7 Family of MicroRNAs in CD4+ T Cells Alters IL-10 Expression
Swaminathan, S., Suzuki, K., Seddiki, N., Kaplan, W. H., Cowley, M. J., Hood, C. L., Clancy, J. L., Murray, D. D., Méndez, C., Gelgor, L., et al. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1101196 · Cited by 142
“Tregs were stained and sorted using standard protocols (17) on a BD FACSAria flow cytometer.”
MethodSelf-citationResidual inflammation and viral reservoirs
Massanella, M., Fromentin, R., & Chomont, N. (2015) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000230 · Cited by 146
“The suppressive capacity of Tregs is influenced by several factors, such as IL-2, inhibitory cytokines [IL-10, transforming growth factor beta (TGF-b) or IL-35[ and immune checkpoints such as CTLA-4 and LAG-3 [84,85].”
BackgroundInfluentialRegulatory T Cells in Tumor Microenvironment and Approach for Anticancer Immunotherapy
Kim, J.-H., Kim, B. S., & Lee, S. (2020) · Immune Network · doi:10.4110/in.2020.20.e4 · Cited by 147
“CD4+CD25+ Tregs expressing low levels of CD127 (the α-chain of the IL-7 receptor) are regarded as functional Tregs with suppressive activities (29,30).”
BackgroundCD49d provides access to “untouched” human Foxp3+ Treg free of contaminating effector cells
Kleinewietfeld, M., Starke, M., Mitri, D. D., Borsellino, G., Battistini, L., Rötzschke, O., & Falk, K. (2008) · Blood · doi:10.1182/blood-2008-04-150524 · Cited by 138
Owen, R. E., Heitman, J. W., Hirschkorn, D. F., Lanteri, M. C., Biswas, H. H., Martin, J. N., Krone, M., Deeks, S. G., & Norris, P. J. (2010) · AIDS · doi:10.1097/qad.0b013e3283377a1e · Cited by 143
“Gating on CD4þCD25þCD127 CD152þ T cells has been shown to define Treg cells [18,19,23,41].”
BackgroundHuman Antigen-Specific Regulatory T Cells Generated by T Cell Receptor Gene Transfer
Brusko, T. M., Koya, R. C., Zhu, S., Lee, M. R., Putnam, A. L., McClymont, S., Nishimura, M. I., Han, S., Chang, L., Atkinson, M. A., et al. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011726 · Cited by 140
“This approach was based on the observation that CD127 is inversely correlated with FOXP3 expression in humans [25,26].”
BackgroundShen, L.-S., Wang, J., Ding-feng, S., Yuan, X.-L., Dong, P., Li, M.-X., Xue, J., Zhang, F., Ge, H.-L., & Xu, D. (2009) · Clinical Immunology · doi:10.1016/j.clim.2008.11.010 · Cited by 140
Hunt, P. W., LANDAY, A. L., Sinclair, E., Martinson, J., Hatano, H., Emu, B., Norris, P. J., Busch, M. P., Martin, J. N., Brooks, C., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015924 · Cited by 139
“Low expression of CD127, as measured in our study, may help distinguish Tregs from activated T cells and is now routinely used with CD25 to quantify the frequency of Tregs with suppressor function [73,74,75].”
MethodSelf-citationCrucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease
Liu, X., Leung, S., Wang, C., Tan, Z., Wang, J., Guo, T. B., Fang, L., Zhao, Y., Wan, B., Qin, X., et al. (2010) · Nature Medicine · doi:10.1038/nm.2077 · Cited by 144
RetractedRapamycin Monotherapy in Patients With Type 1 Diabetes Modifies CD4+CD25+FOXP3+ Regulatory T-Cells
Monti, P., Scirpoli, M., Maffi, P., Piemonti, L., Secchi, A., Bonifacio, E. E., Roncarolo, M., & Battaglia, M. (2008) · Diabetes · doi:10.2337/db08-0138 · Cited by 142
“FOXP3 mean fluorescence intensity of CD4 CD25bright CD127 FOXP3 cells is shown for both PRE and RAPA samples.”
MethodInfluentialHIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy
Gosselin, A., Salinas, T. R. W., Planas, D., Wacleche, V. S., Zhang, Y., Fromentin, R., Chomont, N., Cohen, É. A., Shacklett, B. L., Mehraj, V., et al. (2016) · AIDS · doi:10.1097/qad.0000000000001309 · Cited by 142
“In humans, Tregs can be identified as CD3þCD4þ T cells with a CD25highCD127lowFoxP3þ phenotype [81,95].”
BackgroundIL-7 receptor influences anti-TNF responsiveness and T cell gut homing in inflammatory bowel disease
Belarif, L., Danger, R., Kermarrec, L., Nerrière‐Daguin, V., Pengam, S., Durand, T., Mary, C., Kerdreux, E., Gauttier, V., Kucik, A., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci121668 · Cited by 141
“on a high differential expression level (14, 15).”
The Characterization of Regulatory T-Cell Profiles in Alzheimer’s Disease and Multiple Sclerosis
Ciccocioppo, F., Lanuti, P., Pierdomenico, L., Simeone, P., Bologna, G., Ercolino, E., Buttari, F., Fantozzi, R., Thomas, A., ONOFRJ, M. C., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-45433-3 · Cited by 142
Möbs, C., Slotosch, C., Löffler, H., Jakob, T., Hertl, M., & Pfützner, W. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901379 · Cited by 137
“Studies of Treg cells in the peripheral blood of allergic patients on SIT have primarily focused on the role of Tr1 cells (24, 25, 33), whereas detailed analyses investigating the induction and long-term alteration of CD4+CD25+CD127low Treg cells have not been performed.”
BackgroundInfluentialLee, L., Logronio, K. A., Tu, G. H., Zhai, W., Ni, I., Mei, L., Dilley, J., Yu, J., Rajpal, A., Brown, C. N., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1203795109 · Cited by 137
Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans
Meyers, G., Ng, Y.-S., Bannock, J. M., Lavoie, A., Walter, J. E., Notarangelo, L. D., Kılıç, S. Ş., Aksu, G., Debré, M., Rieux‐Laucat, F., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1102600108 · Cited by 133
Steinborn, A., Haensch, G. M., Mahnke, K., Schmitt, E., Toermer, A., Meuer, S. C., & Sohn, C. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.07.032 · Cited by 133
Metadata
- Authors
- Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M., Selby, W., Alexander, S. I., Nanan, R., Kelleher, A., & de St. Groth, B. F.
- Affiliations
- The University of Sydney (AU)
- 4Department of Paediatrics, University of Sydney, Western Clinical School, Penrith, NSW 2751, Australia
- Rush University Medical Center (US)
- St Vincent's Hospital Sydney (AU)
- Royal Prince Alfred Hospital (AU)
- Children's Hospital at Westmead (AU)
- UNSW Sydney (AU)
- 1Centenary Institute of Cancer Medicine and Cell Biology, Faculty of Medicine, University of Sydney, Newtown, NSW 2042, Australia
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-07-03
- Volume
- 203
- Issue
- 7
- Pages
- 1693-1700
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118333
- OpenAlex
- W2168628806
- Cited by
- 1,512
- References
- 30
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 32 · 2023: 32 · 2022: 44 · 2021: 49 · 2020: 58 · 2019: 75 · 2018: 51 · 2017: 64 · 2016: 74 · 2015: 63 · 2014: 87 · 2013: 92 · 2012: 116
- FWCI
- 45.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Funders
- Crohn's and Colitis Foundation of America
- Crohn's and Colitis Foundation
- Medical Research Council
- National Health and Medical Research Council
- National Institute of Allergy and Infectious Diseases (P01AI055793, AI55793, U19AI055793)
- 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 › IL-33, ST2, and ILC Pathways
- Keywords
- regulatory T cells, CD127, interleukin-2 receptor, Foxp3, CD25, CD4+ T cells, naive T cells, effector memory T cells
- MeSH terms
- Adult, Humans, Infant, Newborn, Lymphocyte Activation, Receptors, Interleukin-2, T-Lymphocyte Subsets, Receptors, Interleukin-7, T-Lymphocytes, Regulatory
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