Cited by 1,512T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisIL-33, ST2, and ILC Pathways

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Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

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Seddiki, Nabila, Santner-Nanan, Brigitte, Martinson, Jeff, Zaunders, John, Sasson, Sarah, Landay, Alan, Solomon, Michael, Selby, Warwick, Alexander, Stephen I., Nanan, Ralph, Kelleher, Anthony, de St. Groth, Barbara Fazekas·2006·The Journal of Experimental Medicine

DOI 10.1084/jem.20060468PMC PMC2118333

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Abstract

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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N aturally A rising CD4+R egulatory T C ells for I mmunologic S elf -T olerance and N egative C ontrol of I mmune R esponses
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An In Vivo IL-7 Requirement for Peripheral Foxp3+ Regulatory T Cell Homeostasis
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“Foxp3 directly suppresses IL-7Ra transcription and thus could lower IL-7 sensitivity (13, 14).”
Natural Tregs and autoimmunity
Cava, A. L. (2009) · Frontiers in bioscience · doi:10.2741/3247 · Cited by 31
The regulatory function of umbilical cord blood CD4+ CD25+ T cells stimulated with anti‐CD3/anti‐CD28 and exogenous interleukin (IL)‐2 or IL‐15
Lee, C., Lin, S., Cheng, P., & Kuo, M. (2009) · Pediatric Allergy and Immunology · doi:10.1111/j.1399-3038.2008.00843.x · Cited by 32
“CD127 (the IL-7 receptor a chain) expression may be tested to better discriminate Treg cells from conventional T cells as it has been reported that Treg cells may have significantly lower CD127 expression (24).”
Background
Regulatory T Cells and IL-17-Producing Cells in Graft-Versus-Host Disease
Teshima, T., Maeda, Y., & Ozaki, K. (2011) · Immunotherapy · doi:10.2217/imt.11.51 · Cited by 32
Revisiting regulatory T cells in type 1 diabetes
Zhang, Y., Bandala‐Sanchez, E., & Harrison, L. C. (2012) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0b013e328355a2d5 · Cited by 32
“receptor alpha chain [39,40] and expression of the Ikaros transcription factor family member Helios [41].”
Background
Immune tolerance and control of CNS autoimmunity: from animal models to MS patients
Cassan, C., & Liblau, R. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04270.x · Cited by 32
CD147 in regulatory T cells
Landskron, J., & Taskén, K. (2013) · Cellular Immunology · doi:10.1016/j.cellimm.2013.04.008 · Cited by 31
High proportions of FOXP 3+ CD 25high T cells in neonates are positively associated with allergic sensitization later in childhood
Strömbeck, A., Rabe, H., Lundell, A., Andersson, K., Johansen, S., Adlerberth, I., Wold, A. E., Hesselmar, B., & Rudin, A. (2014) · Clinical & Experimental Allergy · doi:10.1111/cea.12290 · Cited by 31
CD4+CD25+regulatory T cells in systemic sclerosis and other rheumatic diseases
Amelsfort, J. M. R. M.-V., Walter, G. J., & Taams, L. S. (2011) · Expert Review of Clinical Immunology · doi:10.1586/eci.11.28 · Cited by 31
Regulatory T cell frequencies are increased in preterm infants with clinical early-onset sepsis
Pagel, J., Hartz, A., Figge, J., Gille, C., Eschweiler, S., Petersen, K., Schreiter, L., Hammer, J., Karsten, C. M., Friedrich, D., et al. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12810 · Cited by 31
Regulatory T Cells Show Dynamic Behavior During Late Pregnancy, Delivery, and the Postpartum Period
de Lima, J. J. A. V., Martins, C. G., Nunes, G., de Sousa, M. J. R., Branco, J. C., & Borrego, L. M. (2016) · Reproductive Sciences · doi:10.1177/1933719116676395 · Cited by 31
Effect of thermal processing on T cell reactivity of shellfish allergens - Discordance with IgE reactivity
Abramovitch, J. B., Lopata, A. L., O’Hehir, R. E., & Rolland, J. M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0173549 · Cited by 32
Reduced frequency and functional defects of CD4+CD25highCD127low/− regulatory T cells in patients with unexplained recurrent spontaneous abortion
Luo, L., Zeng, X., Huang, Z., Luo, S., Qin, L., & Li, S. (2020) · Reproductive Biology and Endocrinology · doi:10.1186/s12958-020-00619-7 · Cited by 31
Severe FOXP3+ and Naïve T Lymphopenia in a Non-IPEX Form of Autoimmune Enteropathy Combined With an Immunodeficiency
Zuber, J., Viguier, M. A., Lemaı̂tre, F., Senée, V., Patey, N., Elain, G., Geissmann, F., Fakhouri, F., Ferradini, L., Julier, C., et al. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.02.034 · Cited by 31
Methylprednisolone treatment increases the proportion of the highly suppressive HLA-DR+-Treg-cells in transplanted patients
Seissler, N., Schmitt, E., Hug, F., Sommerer, C., Zeier, M. G., Schaier, M., & Steinborn, A. (2012) · Transplant Immunology · doi:10.1016/j.trim.2012.09.003 · Cited by 31
In vitro-expanded CD4+CD25highFoxp3+ regulatory T cells controls corneal allograft rejection
Guo, X., Jie, Y., Ren, D., Zeng, H., Zhang, Y., He, Y., & Pan, Z. (2012) · Human Immunology · doi:10.1016/j.humimm.2012.08.014 · Cited by 31
Regulatory T-Cell Depletion in Angioimmunoblastic T-Cell Lymphoma
Bruneau, J., Canioni, D., Renand, A., Marafioti, T., Paterson, J. C., Martin‐Garcia, N., Gaulard, P., Delfau‐Larue, M., Hermine, O., Macintyre, E. A., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.100150 · Cited by 31
“15 CD127 weak expression was considered to be a preferred alternative for identification of Treg.16,17 In a multiparametric FC approach, we gated Treg on CD4 , CD25hi, FOXP3 , CD127low expression, and AITL cells on CD4 and CD10 expression (see supplemental Figure S1 at http://ajp.amjpathol.org).”
Influential
Inverse Correlation between CD4 + CD25 High CD127 low/− Regulatory T-Cells and Serum Immunoglobulin A in Patients with New-Onset Ankylosing Spondylitis
Zhao, S.-S., Hu, J.-W., Wang, J., Lou, X.-J., & Zhou, L.-L. (2011) · Journal of International Medical Research · doi:10.1177/147323001103900543 · Cited by 31
Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside
Olivieri, J., Coluzzi, S., Attolico, I., & Olivieri, A. (2011) · The Scientific World JOURNAL · doi:10.1100/2011/924954 · Cited by 32
“These cells were first identified as bearing high levels of the membrane-bound IL-2Ra (CD25), while subsequent refinement included the expression of the transcriptional regulator FoxP3 and lack of the IL7-Ra chain (CD127) as additional molecular markers [25, 26].”
Background
Number and phenotype of rheumatoid arthritis patients’ CD4+CD25hi regulatory T cells are not affected by adalimumab or etanercept
Blache, C. A., Lequerré, T., Roucheux, A., Beutheu, S., Dedreux, I., Jacquot, S., Loët, X. L., Boyer, O., & Vittecoq, O. (2011) · Lara D. Veeken · doi:10.1093/rheumatology/ker183 · Cited by 31
Increased Expression of Programmed Cell Death‐1 in Regulatory T Cells of Patients with Severe Sepsis and Septic Shock: An Observational Clinical Study
Liu, Q., An, L., Qi, Z., Zhao, Y., & Li, C. (2017) · Scandinavian Journal of Immunology · doi:10.1111/sji.12612 · Cited by 31
Immune regulation and anti-cancer activity by lipid inflammatory mediators
Khadge, S., Sharp, J. G., McGuire, T. R., Thiele, G. M., Black, P. N., Dirusso, C., Cook, L. M., Klassen, L. W., & Talmadge, J. E. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.10.026 · Cited by 32
Novel human CD4+ T lymphocyte subpopulations defined by CD300a/c molecule expression
Clark, G. J., Rao, M., Ju, X., & Hart, D. N. J. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0107035 · Cited by 31
“The absence of CD127 on CD4 T lymphocytes has been correlated with Treg cells [23, 24], but CD127 cells were present in all the populations we defined by the level of CMRF-35 epitope expression.”
Background
FoxP3 and Bcl-xL cooperatively promote regulatory T cell persistence and prevention of arthritis development
Haque, R., Lei, F., Xiong, X., Wu, Y., & Song, J. J. (2010) · Arthritis Research & Therapy · doi:10.1186/ar2983 · Cited by 30
Lactose inhibits regulatory T-cell-mediated suppression of effector T-cell interferon-γ and IL-17 production
Paasela, M., Kolho, K., Vaarala, O., & Honkanen, J. K. (2014) · British Journal Of Nutrition · doi:10.1017/s0007114514001998 · Cited by 30
“83 %ofCD4 þ cellswasusedasT eff(24,25) .”
Gitr-Expressing Regulatory T-Cell Subsets are Increased in Tumor-Positive Lymph Nodes from Advanced Breast Cancer Patients as Compared to Tumor-Negative Lymph Nodes
Krausz, L. T., Fischer‐Fodor, E., Major, Z. Z., & Fetică, B. (2012) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463201202500108 · Cited by 30
Human CD8 + CD25 + CD127 low regulatory T cells: microRNA signature and impact on TGF‐β and IL‐10 expression
Rouas, R., Merimi, M., Najar, M., Zein, N. E., Fayyad‐Kazan, M., Berehab, M., Agha, D. M., Bron, D., Burny, A., Rachidi, W., et al. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.28367 · Cited by 32
“Recent reports have shown that the combination of low surface expression of CD127 (the α‐chain of the IL‐7 receptor) with high CD25 expression allows distinguishing between human regulatory and conventional T cells in the thymus, cord blood, adult peripheral blood (PB), and lymph nodes (Hartigan‐O’Connor, Poon, Sincla…”
Background
The making and function of CAR cells
Zabel, M., Tauber, P. A., & Pickl, W. F. (2019) · Immunology Letters · doi:10.1016/j.imlet.2019.06.002 · Cited by 30
Transcriptional regulation of Treg homeostasis and functional specification
Wang, K., & Fu, W. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03534-7 · Cited by 34
Regulatory T Cells in the Tumor Microenvironment
Dadey, R., Workman, C. J., & Vignali, D. A. A. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-49270-0_6 · Cited by 32
Donor reactive regulatory T cells
Feng, G., Chan, T., Wood, K. J., & Bushell, A. (2009) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e32832c58f1 · Cited by 30
Isolation, propagation and characterization of cord blood derived CD4+ CD25+ regulatory T cells
Bresatz, S., Sadlon, T., Millard, D., Zola, H., & Barry, S. C. (2007) · Journal of Immunological Methods · doi:10.1016/j.jim.2007.06.006 · Cited by 30
The effect of aging on T-regulatory cell frequency in HIV infection
Tenorio, A. R., Spritzler, J., Martinson, J., Gichinga, C. N., Pollard, R. B., Lederman, M. M., Kalayjian, R. C., & LANDAY, A. L. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.10.001 · Cited by 30
Self-citation
Regulatory T cells as potential immunotherapy in allergy
Wing, K., & Sakaguchi, S. (2006) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/01.all.0000246625.79988.12 · Cited by 30
Regulatory T Cells in Colorectal Cancer: From Biology to Prognostic Relevance
Mougiakakos, D. (2011) · Cancers · doi:10.3390/cancers3021708 · Cited by 30
“Ligands for CCR4 (e.g., CCL17 and/or CCL22) were in contrast to IL-6 and TGF-β not highly expressed in the tumor tissue, altogether indicating a conversion from CD8 + Tconvs rather than a tumor directed migration as the cause for the observed infiltration.”
BackgroundInfluential
Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells
Mesquita, D., Cruvinel, W. D. M., Araújo, J. A. P., Pucci, F. V. C., Salmazi, K. C., Kallás, E., & Andrade, L. E. C. (2010) · Scandinavian Journal of Rheumatology · doi:10.3109/03009742.2010.489229 · Cited by 30
“Alternative putatively reliable surface phenotypes for Treg cells include CD25+CD127low/Ø, CD25+CD45RA+, and CD4+CD39+ (5, 6, 35, 36).”
BackgroundMethod
Association of two clones allows for optimal detection of human FOXP3
Presicce, P., Moreno‐Fernandez, M. E., Lages, C. S., Orsborn, K. I., & Chougnet, C. A. (2010) · Cytometry Part A · doi:10.1002/cyto.a.20875 · Cited by 29
“Anti-CD127 (R34.”
Influential
The FOXP3+ subset of human CD4+CD8+ thymocytes is immature and subject to intrathymic selection
Tuovinen, H., Pekkarinen, P. T., Rossi, L. H., Mattila, I. P., & Arstila, T. P. (2008) · Immunology and Cell Biology · doi:10.1038/icb.2008.36 · Cited by 30
Cutting Edge: Human CD4−CD8− Thymocytes Express FOXP3 in the Absence of a TCR
Tuovinen, H., Kekäläinen, E., Rossi, L. H., Puntila, J., & Arstila, T. P. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.6.3651 · Cited by 30
Efforts of the human immune system to maintain the peripheral CD8+ T cell compartment after childhood thymectomy
Zlamy, M., Almanzar, G., Parson, W., Schmidt, C., Leierer, J., Weinberger, B., Jeller, V., Unsinn, K., Eyrich, M., Würzner, R., et al. (2016) · Immunity & Ageing · doi:10.1186/s12979-016-0058-z · Cited by 29
“On separated subsets of human peripheral CD8+ T cells, almost 100 % of naive (CD45RA + CCR7+) and central memory (CD45R0 + CCR7+) T cells and 60–70 % of effector memory (CD45R0 + CCR7-), but only <20 % of terminally differentiated (CD45RA + CCR7-) T cells express CD127 [50–52] which agrees with our results.”
Result
Successful generation of primary virus-specific and anti-tumor T-cell responses from the naive donor T-cell repertoire is determined by the balance between antigen-specific precursor T cells and regulatory T cells
Jedema, I., van de Meent, M., Pots, J. M., Kester, M. G. D., van der Beek, M. T., & Falkenburg, J. H. F. (2011) · Haematologica · doi:10.3324/haematol.2010.039099 · Cited by 29
The effect of various disease-modifying anti-rheumatic drugs on the suppressive function of CD4+CD25+ regulatory T cells
Oh, J. S., Kim, Y., Lee, S., So, M. W., Choi, S. W., Lee, C., & Yoo, B. (2012) · Rheumatology International · doi:10.1007/s00296-012-2365-9 · Cited by 29
CD4+CD25+CD127− assessment as a surrogate phenotype for FOXP3+ regulatory T cells in HIV‐1 infected viremic and aviremic subjects
Saison, J., Demaret, J., Venet, F., Chidiac, C., Malcus, C., Poitevin‐Later, F., Tardy, J., Ferry, T., & Monneret, G. (2012) · Cytometry Part B Clinical Cytometry · doi:10.1002/cyto.b.21047 · Cited by 29
“A good correlation between these two phenotypes was reported in healthy subjects (13) and in septic patients (14).”
Background
The impact of allergen exposure and specific immunotherapy on circulating blood cells in allergic rhinitis
Jordakieva, G., & Jensen‐Jarolim, E. (2018) · World Allergy Organization Journal · doi:10.1186/s40413-018-0197-0 · Cited by 29
“Circulating Treg numbers did not differ between healthy subjects and in AR outside of allergen exposure [32], with an increase of Treg cells in nasal mucosa after allergen challenge and during allergen season [33, 34].”
Background
Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3− T cells in complete DiGeorge anomaly
Chinn, I. K., Milner, J. D., Scheinberg, P., Douek, D. C., & Markert, M. L. (2013) · Clinical & Experimental Immunology · doi:10.1111/cei.12088 · Cited by 29
Induction of contact‐dependent CD8+ regulatory T cells through stimulation with staphylococcal and streptococcal superantigens*
Taylor, A. L., Cross, E. L. A., & Llewelyn, M. (2011) · Immunology · doi:10.1111/j.1365-2567.2011.03529.x · Cited by 29
Interleukin-7 matures suppressive CD127+ forkhead box P3 (FoxP3)+ T cells into CD127- CD25high FoxP3+ regulatory T cells
Caro, V. D., D’Anneo, A., Phillips, B. E., Engman, C., Harnaha, J., Lakomy, R., Styche, A. J., Trucco, M., & Giannoukakis, N. (2011) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2011.04334.x · Cited by 29
Phase- and Stage-Related Proportions of T Cells Bearing the Transcription Factor FOXP3 Infiltrate Primary Melanoma
Panfilis, G. D., Campanini, N., Santini, M., Mori, G., Tognetti, E., Maestri, R., Lombardi, M., Froio, E., Ferrari, D., & Ricci, R. (2007) · Journal of Investigative Dermatology · doi:10.1038/sj.jid.5701046 · Cited by 30
“, 2005; Banham, 2006); moreover, FOXP3þ cells may show regulatory activity irrespective of their CD25 expression (Banham, 2006; Liu et al., 2006; Seddiki et al., 2006).”
Background
Triptolide, a Component of Chinese Herbal Medicine, Modulates the Functional Phenotype of Dendritic Cells
Liu, Y., Chen, Y., Lamb, J. R., & Tam, P. K. H. (2007) · Transplantation · doi:10.1097/01.tp.0000289990.55668.0d · Cited by 29
“The studies highlight the importance of Foxp3 and reduced CD127 expression as Treg cell markers that function independently of CD25 expression (19, 20).”
Background
Decreased expression of Runx1 and lowered proportion of Foxp3+CD25+CD4+regulatory T cells in systemic sclerosis
Kataoka, H., Yasuda, S., Fukaya, S., Oku, K., Horita, T., Atsumi, T., & Koike, T. (2014) · Modern Rheumatology · doi:10.3109/14397595.2014.899736 · Cited by 29
Human secondary lymphoid organs typically contain polyclonally-activated proliferating regulatory T cells
Peters, J. H., Koenen, H. J. P. M., Fasse, E., Tijssen, H. J., IJzermans, J. N. M., Groenen, P. J. T. A., Schaap, N. P., Kwekkeboom, J., & Joosten, I. (2013) · Blood · doi:10.1182/blood-2013-03-489443 · Cited by 29
“Human naive and memory CD4 T cells express the IL-7 receptor (CD127), while in contrast, this receptor is lacking on human CD4CD25 Tregs.(45,46) The absence of CD127 expression might explain the lack of a4b1 on Tregs.”
Background
T regulatory cell phenotypes in peripheral blood and bronchoalveolar lavage from non‐asthmatic and asthmatic subjects
Baatjes, A. J., Smith, S. G., WATSON, R. M., Howie, K. J., Murphy, D. M., Larché, M., Denburg, J. A., Inman, M. D., & O’Byrne, P. M. (2015) · Clinical & Experimental Allergy · doi:10.1111/cea.12594 · Cited by 29
IL-7 uniquely maintains FoxP3+ adaptive Treg cells that reverse diabetes in NOD mice via integrin-β7-dependent localization
Li, C.-R., Deiro, M. F., Godebu, E., & Bradley, L. M. (2011) · Journal of Autoimmunity · doi:10.1016/j.jaut.2011.06.002 · Cited by 28
“Although ex vivo expanded nTreg cells can control autoimmune responses in the NOD model with remarkable success [5, 39], it is impossible to unequivocally isolate cells with regulatory function from human peripheral blood on the basis of the currently used markers, high levels of CD25 combined with low levels of IL-7R…”
Background
Polyclonal Expansion of Human CD4+CD25+ Regulatory T Cells
Hoffmann, P., Eder, R., & Edinger, M. (2010) · Methods in molecular biology · doi:10.1007/978-1-60761-869-0_2 · Cited by 29
Ex vivo expanded regulatory T cells CD4+CD25+FoxP3+CD127Low develop strong immunosuppressive activity in patients with remitting-relapsing multiple sclerosis
Lifshitz, G. V., Zhdanov, D. D., Lokhonina, А. V., Eliseeva, D. D., Lyssuk, E. Y., Завалишин, И. А., & Быковская, С. Н. (2016) · Autoimmunity · doi:10.1080/08916934.2016.1199020 · Cited by 29
“Tregs express low levels of the IL-7 receptor (CD127) at their cell surface [12,13].”
Background
Combination of IL-2, rapamycin, DNA methyltransferase and histone deacetylase inhibitors for the expansion of human regulatory T cells
Miyara, M., Chader, D., Burlion, A., Goldstein, J. D., Sterlin, D., Norol, F., Trebeden‐Negre, H., Claër, L., Sakaguchi, S., Marodon, G., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.10914 · Cited by 29
“Other groups have focused on CD4+CD25+CD127low/- cells because this phenotypic definition indeed encompasses all FOXP3 expressing CD4+ T cells [31, 32].”
Immune cell and cytokine patterns in children with type 1 diabetes mellitus undergoing a remission phase: A longitudinal study
Fitas, A. L., Martins, C. G., Borrego, L. M., Lopes, L., Jörns, A., Lenzen, S., & Limbert, C. (2018) · Pediatric Diabetes · doi:10.1111/pedi.12671 · Cited by 29
“5 (clone SK3, Biolegend) and anti-CD127 AlexaFluor647 (clone A019D5, Biolegend) (Additional information in Figure S1, Supporting Information).(21,22) 964 FITAS ET AL.”
Regulatory T-cell dynamics with abatacept treatment in rheumatoid arthritis
Langdon, K., & Haleagrahara, N. (2018) · International Reviews of Immunology · doi:10.1080/08830185.2018.1465943 · Cited by 30
Prolonged lymphocyte depletion by single-dose rabbit anti-thymocyte globulin and alemtuzumab in kidney transplantation
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Combined T regulatory cell and Th2 expression profile identifies children with cow's milk allergy
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Disengaging the IL-2 Receptor with Daclizumab Enhances IL-7–Mediated Proliferation of CD4+ and CD8+ T Cells
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“In resting T cells, CD25 was mainly confined to a small subset of CD4+ T cells which did not express CD127, consistent with a regulatory T-cell phenotype (14,15).”
Background
A quest for universal anti-SARS-CoV-2 T cell assay: systematic review, meta-analysis, and experimental validation
Binayke, A., Zaheer, A., Vishwakarma, S., Singh, S., Sharma, P., Chandwaskar, R., Gosain, M., Raghavan, S., Murugesan, D. R., Kshetrapal, P., et al. (2024) · npj Vaccines · doi:10.1038/s41541-023-00794-9 · Cited by 28
High content cellular immune profiling reveals differences between rhesus monkeys and men
Magalhaes, I., Vudattu, N. K., Ahmed, R. K. S., Kühlmann‐Berenzon, S., Ngo, Y., Sizemore, D. R., Wehlin, L., Weichold, F., Andersson, J., Skeiky, Y. A. W., et al. (2010) · Immunology · doi:10.1111/j.1365-2567.2010.03284.x · Cited by 28
CD4 T Cells Mediate Both Positive and Negative Regulation of the Immune Response to HIV Infection: Complex Role of T Follicular Helper Cells and Regulatory T Cells in Pathogenesis
Phetsouphanh, C., Xu, Y., & Zaunders, J. J. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00681 · Cited by 27
“that the IL7Rα (CD127) is expressed at low to intermediate levels on the surface of Tregs and the combination of CD25+ CD127lo can be used to distinguish Treg from other CD4 subsets; CD25+ CD127low Tregs contain high amounts of Foxp3 and can suppress immune responses in vitro (51, 52).”
BackgroundInfluentialSelf-citation
Generation of Human Alloantigen-Specific Regulatory T Cells under Good Manufacturing Practice-Compliant Conditions for Cell Therapy
Chera, M., Hamel, Y., Baillou, C., Touil, S., Guillot‐Delost, M., Charlotte, F., Kossir, L., Simonin, G., Maury, S., Cohen, J. L., et al. (2014) · Cell Transplantation · doi:10.3727/096368914x683566 · Cited by 28
“For these reasons, the development of specific cell-based therapies may offer alternative approaches to prevent and/or to control severe GVHD. Natural regulatory T cells (Tregs) are defined by constitutive expression of high levels of the transcription factor forkhead box P3 (FOXP3), which is critical for their develo…”
BackgroundInfluential
Analysis of FOXP3+ regulatory T cell subpopulations in peripheral blood and tissue of patients with systemic lupus erythematosus
Schmidt, A., Rieger, C. C., Venigalla, R. K., Éliás, S., Max, R., Lorenz, H., Gröne, H., Krammer, P. H., & Kuhn, A. (2017) · Immunologic Research · doi:10.1007/s12026-017-8904-4 · Cited by 29
“Although expression of FOXP3 simultaneously with a high-level expression of CD25 identifies a largely pure Treg population, additional markers have been suggested to assure even better exclusion of activated conventional T cells, such as absence of CD49d [5] or CD127 [6] on Tregs; however, the latter does not enable d…”
Background
Ex vivo expanded natural regulatory T cells from patients with end-stage renal disease or kidney transplantation are useful for autologous cell therapy
Landwehr-Kenzel, S., Zobel, A., Hoffmann, H., Landwehr, N., Schmueck‐Henneresse, M., Schachtner, T., Roemhild, A., & Reinke, P. (2018) · Kidney International · doi:10.1016/j.kint.2018.01.021 · Cited by 28
The Cytokine Receptor IL-7Rα Impairs IL-2 Receptor Signaling and Constrains the In Vitro Differentiation of Foxp3+ Treg Cells
Waickman, A. T., Keller, H. R., Kim, T., Luckey, M. A., Tai, X., Hong, C., Molina-Parı́s, C., Walsh, S. T. R., & Park, J. (2020) · iScience · doi:10.1016/j.isci.2020.101421 · Cited by 28
“Here, we considered that Foxp3+ Treg cells are uniquely low in IL-7Ra expression compared with conventional CD4 T cells (Figure 2A) (Seddiki et al., 2006; Liu et al., 2006; Cozzo et al., 2003).”
BackgroundResultInfluential
Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis
Sasson, S. C., Zaunders, J., Nahar, K. J., Munier, C. M. L., Fairfax, B. P., Olsson-Brown, A. C., Jolly, C., Read, S. A., Ahlenstiel, G., Palendira, U., et al. (2020) · Clinical & Experimental Immunology · doi:10.1111/cei.13502 · Cited by 27
Self-citation
Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis
Adriawan, I. R., Atschekzei, F., Dittrich‐Breiholz, O., Garantziotis, P., Hirsch, S., Risser, L. M., Kosanke, M., Schmidt, R. E., Witte, T., & Sogkas, G. (2021) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2021-220955 · Cited by 28
Regulatory T-Cells and Multiple Myeloma: Implications in Tumor Immune Biology and Treatment
Hadjiaggelidou, C., & Katodritou, E. (2021) · Journal of Clinical Medicine · doi:10.3390/jcm10194588 · Cited by 28
Advanced flowcytometric analysis of regulatory T cells: CD127 downregulation early post stem cell transplantation and altered Treg/CD3+CD4+-ratio in severe GvHD or relapse
Bremm, M., Huenecke, S., Lehrnbecher, T., Ponstingl, E., Mueller, R., Heinze, A., Bug, G., Quaiser, A., Kapinsky, M., Brehm, C., et al. (2011) · Journal of Immunological Methods · doi:10.1016/j.jim.2011.07.018 · Cited by 28
Higher proportions of circulating FOXP3+ and CTLA-4+ regulatory T cells are associated with lower fractions of memory CD4+ T cells in infants
Rabe, H., Lundell, A., Andersson, K., Adlerberth, I., Wold, A. E., & Rudin, A. (2011) · Journal of Leukocyte Biology · doi:10.1189/jlb.0511244 · Cited by 28
“Staining for CD25 and CD127 to identify Tregs [38] and study their expression of CTLA-4 in infants could have been a better approach.”
Background
Regulatory T cells: balancing protection versus pathology
Rakebrandt, N., Lambert, K., & Joller, N. (2016) · Swiss Medical Weekly · doi:10.4414/smw.2016.14343 · Cited by 30
The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1) proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis
Michaëlsson, J., Barbosa, H. M. R., Jordan, K. A., Chapman, J. M., Brunialti, M. K. C., Neto, W. K., Nukui, Y., Sabino, É. C., Chieia, M. A. T., Oliveira, A. S. B., et al. (2008) · BMC Immunology · doi:10.1186/1471-2172-9-41 · Cited by 28
“In addition, it was recently demonstrated that TReg cells are characterized by low levels of the IL-7Rα (CD127low) [40-42], which together with CD25 help to distinguish TReg cells from activated normal CD4+ T cells in healthy individuals.”
Background
TGF-β and IL-10 Production by HIV-Specific CD8+ T Cells Is Regulated by CTLA-4 Signaling on CD4+ T Cells
Elrefaei, M., Burke, C. M., Baker, C. A. R., Jones, N. G., Bousheri, S., Bangsberg, D. R., & Cao, H. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008194 · Cited by 28
“The lack of CD127 expression on FOXP3 positive CD4+ T cells is used to distinguish between regulatory and effector T cells [48,49].”
Delta-like 1–Mediated Notch Signaling Enhances the In Vitro Conversion of Human Memory CD4 T Cells into FOXP3-Expressing Regulatory T Cells
Mota, C., Silva, V. M. D. S., Pires, A. R., Matoso, P., Victorino, R. M. M., Sousa, A. E., & Caramalho, Í. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1400198 · Cited by 27
“from the starting populations (25, 26) (Supplemental Fig.”
Background
Pharmacodynamic Monitoring of Mammalian Target of Rapamycin Inhibition by Phosphoflow Cytometric Determination of p70S6 Kinase Activity
Hoerning, A., Wilde, B., Wang, J., Tebbe, B., Jing, L., Wang, X., Jian, F., Zhu, J.-Q., Dolff, S., Kribben, A., et al. (2014) · Transplantation · doi:10.1097/tp.0000000000000273 · Cited by 27
Wasp venom immunotherapy induces activation and homing of CD4+CD25+ forkhead box protein 3–positive regulatory T cells controlling TH1 responses
Kerstan, A., Albert, C., Klein, D., Bröcker, E., & Trautmann, A. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.11.025 · Cited by 28
Regulatory T-cell adoptive immunotherapy: potential for treatment of autoimmunity
Wright, G. P., Ehrenstein, M. R., & Stauss, H. J. (2011) · Expert Review of Clinical Immunology · doi:10.1586/eci.10.96 · Cited by 27
Optimizing human Treg immunotherapy by Treg subset selection and E-selectin ligand expression
Donnelly, C., Dykstra, B. J., Mondal, N., Huang, J., Kaskow, B. J., Griffin, R. L., Sackstein, R., & Baecher‐Allan, C. (2018) · Scientific Reports · doi:10.1038/s41598-017-17981-z · Cited by 28
Diverse functions and mechanisms of regulatory T cell in ischemic stroke
Wu, Y., Li, J., Shou, J., Zhang, W., & Chen, C. (2021) · Experimental Neurology · doi:10.1016/j.expneurol.2021.113782 · Cited by 26
OMIP ‐024: Pan‐leukocyte immunophenotypic characterization of PBMC subsets in human samples
Moncunill, G., Han, H., Dobaño, C., McElrath, M. J., & Rosa, S. C. D. (2014) · Cytometry Part A · doi:10.1002/cyto.a.22580 · Cited by 28
Current understanding of HIV-1 and T-cell adaptive immunity: Progress to date
Mohan, T., Bhatnagar, S., Gupta, D. L., & Rao, D. N. (2014) · Microbial Pathogenesis · doi:10.1016/j.micpath.2014.06.003 · Cited by 29
APC dysfunction is correlated with defective suppression of T cell proliferation in human type 1 diabetes
Jin, Y., Chen, X., Podolsky, R. H., Hopkins, D., Makala, L., Muir, A., & She, J. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.10.005 · Cited by 27
Expansion of Allospecific Regulatory T Cells After Anergized, Mismatched Bone Marrow Transplantation
DAVIES, J. K., Nadler, L. M., & Guinan, E. C. (2009) · Science Translational Medicine · doi:10.1126/scitranslmed.3000153 · Cited by 27
Quantitative and qualitative analysis of regulatory T cells in B cell chronic lymphocytic leukemia
Mpakou, V., Ioannidou, H.-D., Konsta, E., Vikentiou, M., Spathis, A., Kontsioti, F., Kontos, C. K., Velentzas, A. D., Papageorgiou, S. G., Vasilatou, D., et al. (2017) · Leukemia Research · doi:10.1016/j.leukres.2017.07.004 · Cited by 27
Blocking Formation of the Stable HIV Reservoir: A New Perspective for HIV-1 Cure
Goonetilleke, N. P., Clutton, G., Swanstrom, R., & Joseph, S. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01966 · Cited by 27
Administration of a polyvalent mechanical bacterial lysate to elderly patients with COPD: Effects on circulating T, B and NK cells
Lanzilli, G., Traggiai, E., Braido, F., Garelli, V., Folli, C., Chiappori, A., Riccio, A., Bazurro, G., Agazzi, A., Magnani, A., et al. (2012) · Immunology Letters · doi:10.1016/j.imlet.2012.11.009 · Cited by 27
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Immunology of pregnancy
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CD4+CD25-FoxP3+T cells: a distinct subset or a heterogeneous population?
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“naïve CD4þCD25– T cells transiently express CD25, but unlike Tregs they show high CD127 expression.(13)”
Background
Regulatory T cells in inflammation and resolution of acute lung injury
Wang, L., Jiang, W., Wang, X., Tong, L., & Song, Y. (2022) · The Clinical Respiratory Journal · doi:10.1111/crj.13527 · Cited by 25
Regulatory T-cells in chronic lymphocytic leukemia: actor or innocent bystander?
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“These limitations have been somewhat overcome by the demonstration that CD127, the alpha chain of the IL-7 receptor, when used in conjunction with IL-25 expression effectively distinguishes Foxp3+ Teff from Foxp3+ Treg with functional Treg confined to the CD25+CD127 population [23,24].”
Background
Clinical‐grade preparation of human natural regulatory T‐cells encoding the thymidine kinase suicide gene as a safety gene
Guillot‐Delost, M., Cheraï, M., Hamel, Y., Rosenzwajg, M., Baillou, C., Simonin, G., Leclercq, V., Mariotti‐Ferrandiz, E., Six, A., Bon‐Durand, V., et al. (2008) · The Journal of Gene Medicine · doi:10.1002/jgm.1220 · Cited by 26
“As shown in Figure 3B, MACS-sorted CD25+ cells cultured in the presence of rapamycin remained CD127low/− and CD25high at day-21, whereas CD4+CD25− cells cultured under the same conditions acquired CD25 and remained CD127+.”
BackgroundInfluential
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PI16 is expressed by a subset of human memory Treg with enhanced migration to CCL17 and CCL20
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Impaired function of regulatory T cells in cord blood of children of allergic mothers
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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: Seddiki, Nabila
Zaunders, John
Sasson, Sarah
Landay, Alan
Solomon, Michael
Alexander, Stephen I.
Nanan, Ralph
Kelleher, Anthony
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
DOI: 10.1084/jem.20060468
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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Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

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