Cited by 73T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisIL-33, ST2, and ILC Pathways

Single-Cell Analysis of the Human T Regulatory Population Uncovers Functional Heterogeneity and Instability within FOXP3+ Cells

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d’Hennezel, Eva, Yurchenko, Ekaterina, Sgouroudis, Evridiki, Hay, Valérie, Piccirillo, Ciriaco A·2011·The Journal of Immunology

Abstract

Natural FOXP3+CD4+CD25High regulatory T cells are critical in immunological self-tolerance. Their characterization in humans is hindered by the failure to discriminate these cells from activated effector T cells in inflammation. To explore the relationship between FOXP3 expression and regulatory function at the clonal level, we used a single-cell cloning strategy of CD25-expressing CD4+ T cell subsets from healthy human donors. Our approach unveils a functional heterogeneity nested within CD4+CD25HighFOXP3+ T cells, and typically not revealed by conventional bulk assays. Whereas most cells display the canonical regulatory T (Treg) cell characteristics, a significant proportion of FOXP3+ T cells is compromised in its suppressive function, despite the maintenance of other phenotypic and functional regulatory T hallmark features. In addition, these nonsuppressive FOXP3+ T cells preferentially emerge from the CD45RO+ memory pool, and arise as a consequence of a rapid downregulation of FOXP3 expression upon T cell reactivation. Surprisingly, these dysfunctional Treg cells with unstable FOXP3 expression do not manifest overt plasticity in terms of inflammatory cytokine secretion. These results open a path to an extensive study of the functional heterogeneity of CD4+CD25HighFOXP3+ Treg cells and warrant caution in the sole use of FOXP3 as a clinical marker for monitoring of immune regulation in humans.

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  • The strong activation and expansion of Treg cells during the rejection episode suggests engagement of strong immunosuppression in response to inflammation.

    “A strong activation and expansion of Treg cells, with higher expression of Foxp3, was evident during the rejection episode, suggesting the engagement of strong immunosuppression in response to inflammation42.”

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Authors
d’Hennezel, E., Yurchenko, E., Sgouroudis, E., Hay, V., & Piccirillo, C. A.
Affiliations
  • Department of Microbiology and Immunology, McGill University , Montreal, Quebec H3A 2B4 ,
  • McGill University Health Centre (CA)
Corresponding author
Piccirillo, Ciriaco A
Venue
The Journal of Immunology
Published
2011-06
Volume
186
Issue
12
Pages
6788-6797
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
OpenAlex
W2098155999
Cited by
73
References
61
Citations by year
2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 1 · 2017: 8 · 2016: 6 · 2015: 12 · 2014: 8 · 2013: 12 · 2012: 12
FWCI
4.54
Type
journal article
Language
en
Open access
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • McGill University
  • McGill University Health Centre
  • Canadian Institutes of Health Research (MOP84041)
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, Foxp3, functional heterogeneity, suppressive function, CD4+CD25high T cells, CD45RO+ memory T cells, T cell reactivation, T cell plasticity, self-tolerance, single-cell cloning
MeSH terms
Clone Cells, Humans, Immunologic Memory, Lymphocyte Activation, Biomarkers, Antigens, CD, Self Tolerance, Inflammation Mediators, T-Lymphocytes, Regulatory, Forkhead Transcription Factors

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