CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells
Open accessAbstract
Regulatory T (T reg) cells are critical regulators of immune tolerance. Most T reg cells are defined based on expression of CD4, CD25, and the transcription factor, FoxP3. However, these markers have proven problematic for uniquely defining this specialized T cell subset in humans. We found that the IL-7 receptor (CD127) is down-regulated on a subset of CD4(+) T cells in peripheral blood. We demonstrate that the majority of these cells are FoxP3(+), including those that express low levels or no CD25. A combination of CD4, CD25, and CD127 resulted in a highly purified population of T reg cells accounting for significantly more cells that previously identified based on other cell surface markers. These cells were highly suppressive in functional suppressor assays. In fact, cells separated based solely on CD4 and CD127 expression were anergic and, although representing at least three times the number of cells (including both CD25(+)CD4(+) and CD25(-)CD4(+) T cell subsets), were as suppressive as the "classic" CD4(+)CD25(hi) T reg cell subset. Finally, we show that CD127 can be used to quantitate T reg cell subsets in individuals with type 1 diabetes supporting the use of CD127 as a biomarker for human T reg cells.
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Treg cells are required for peripheral tolerance and can be distinguished from conventional CD4+ T cells based on constitutive high expression of CD25 and low expression of CD127.
“Treg cells are required for peripheral tolerance and can be distinguished from conventional CD4+ T cells based on the constitutive high expression of the IL-2 receptor alpha chain (CD25) and the low expression of the IL-7 receptor alpha chain (CD127) (Figure 8A) [134].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [134]
The Abstract and Discussion describe Treg cells as important for immune tolerance and support low CD127 combined with CD25 as a way to identify human Treg cells. But the Results (Analysis of novel T reg cell–specific cell surface molecules; page unavailable) and Discussion also identify FoxP3-positive or suppressive CD127-low cells with low or absent CD25. Thus, constitutively high CD25 is not a distinguishing feature of all Treg cells in this paper. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMany studies frequently use solely FoxP3 or one or two additional markers as substitutes to identify Tregs, but this approach lacks accuracy and precision.
“Many studies frequently use solely FoxP3 or just one or two additional markers (e.g., CD25high and CD127low) as substitutes to identify Tregs, but this approach lacks accuracy and precision [164].”
From Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review (2024) · cites this paper as [164]
The Abstract and Discussion describe limitations of identifying human Tregs with FoxP3 or CD25 alone, including Tregs missed by CD25-based selection. But the Results call CD4+CD25+CD127lo/− the best cell-surface marker combination and say it yields a highly purified FoxP3+ population. The paper therefore does not support the claim’s blanket dismissal of the cited marker combination as inaccurate and imprecise. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe best accepted combination of surface markers for Tregs is high expression of CD25 and low expression of CD127.
“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 [134]
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References 54 · Cited by 2,606
- Authors
- Liu, W., Putnam, A. L., Xu-yu, Z., Szot, G. L., Lee, M. R., Zhu, S., Gottlieb, P. A., Kapranov, P., Gingeras, T. R., de St. Groth, B. F., Clayberger, C., Soper, D. M., Ziegler, S. F., & Bluestone, J. A.
- Affiliations
- University of California, San Francisco (US)
- University of Colorado Health (US)
- 3Affymetrix, Inc., Santa Clara, CA 95051
- 4Centenary Institute of Cancer Medicine and Cell Biology, Faculty of Medicine, University of Sydney, New South Wales 2042 Australia
- Stanford Medicine (US)
- University of Washington (US)
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-07-03
- Volume
- 203
- Issue
- 7
- Pages
- 1701-1711
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118339
- OpenAlex
- W2156964052
- Cited by
- 2,606
- References
- 54
- Citations by year
- 2026: 51 · 2025: 53 · 2024: 95 · 2023: 80 · 2022: 87 · 2021: 84 · 2020: 109 · 2019: 143 · 2018: 107 · 2017: 114 · 2016: 115 · 2015: 129 · 2014: 139 · 2013: 148 · 2012: 203
- FWCI
- 68.54
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- cc-by-nc-sa
- 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)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institute of Allergy and Infectious Diseases (AI048779, R01AI048779)
- National Institute of Diabetes and Digestive and Kidney Diseases (U19DK061934, P30DK063720)
- 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 › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- regulatory T cells, CD127, IL-7 receptor, Foxp3, CD25, CD4+ T cells, Treg suppressive function, type 1 diabetes, immune tolerance
- MeSH terms
- Adolescent, Adult, Cells, Cultured, Diabetes Mellitus, Type 1, Humans, Immunologic Memory, Middle Aged, Receptors, Interleukin-2, Biomarkers, CD4 Lymphocyte Count, Receptors, Interleukin-7, T-Lymphocytes, Regulatory, Forkhead Transcription Factors
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