Plasticity of Human Regulatory T Cells in Healthy Subjects and Patients with Type 1 Diabetes
Open accessAbstract
Regulatory T cells (Tregs) constitute an attractive therapeutic target given their essential role in controlling autoimmunity. However, recent animal studies provide evidence for functional heterogeneity and lineage plasticity within the Treg compartment. To understand better the plasticity of human Tregs in the context of type 1 diabetes, we characterized an IFN-γ–competent subset of human CD4+CD127lo/−CD25+ Tregs. We measured the frequency of Tregs in the peripheral blood of patients with type 1 diabetes by epigenetic analysis of the Treg-specific demethylated region (TSDR) and the frequency of the IFN-γ+ subset by flow cytometry. Purified IFN-γ+ Tregs were assessed for suppressive function, degree of TSDR demethylation, and expression of Treg lineage markers FOXP3 and Helios. The frequency of Tregs in peripheral blood was comparable but the FOXP3+IFN-γ+ fraction was significantly increased in patients with type 1 diabetes compared to healthy controls. Purified IFN-γ+ Tregs expressed FOXP3 and possessed suppressive activity but lacked Helios expression and were predominately methylated at the TSDR, characteristics of an adaptive Treg. Naive Tregs were capable of upregulating expression of Th1-associated T-bet, CXCR3, and IFN-γ in response to IL-12. Notably, naive, thymic-derived natural Tregs also demonstrated the capacity for Th1 differentiation without concomitant loss of Helios expression or TSDR demethylation.
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The earliest clinical trials targeting the TGF-β pathway for cancer treatment used a tumor vaccine for non-small cell lung carcinoma genetically modified to include anti-sense TGF-β2 RNA.
“Indeed, the earliest clinical trials targeting the TGF-β pathway for cancer treatment were designed to potentiate anti-tumor immunity using a tumor vaccine for non-small lung carcinoma, genetically modified by including an anti-sense TGF-β2 RNA370.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [370]
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Self-citation
- Authors
- McClymont, S. A., Putnam, A. L., Lee, M. R., Esensten, J. H., Liu, W., Hulme, M. A., Hoffmüller, U., Baron, U., Olek, S., Bluestone, J. A., & Brusko, T. M.
- Affiliations
- University of California, San Francisco (US)
- University of Florida (US)
- Epiontis , GmbH, 12489 Berlin ,
- Corresponding author
- Liu, Weihong
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-04-01
- Volume
- 186
- Issue
- 7
- Pages
- 3918-3926
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC3091943
- OpenAlex
- W2150901150
- Cited by
- 428
- References
- 44
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 29 · 2023: 13 · 2022: 28 · 2021: 25 · 2020: 29 · 2019: 25 · 2018: 26 · 2017: 22 · 2016: 35 · 2015: 28 · 2014: 30 · 2013: 41 · 2012: 35
- FWCI
- 17.59
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (P01AI035294, U01AI102011, U19AI056388)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- regulatory T cells, Treg plasticity, type 1 diabetes, interferon-gamma, DNA methylation, Foxp3, Helios, suppressive function, Th1 differentiation, IL-12, autoimmunity
- MeSH terms
- Adolescent, Adult, Cells, Cultured, Child, Diabetes Mellitus, Type 1, Female, Humans, Interferon-gamma, Lymphocyte Activation, Male, Middle Aged, T-Lymphocyte Subsets, Inflammation Mediators, DNA Methylation, Cell Proliferation, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Young Adult
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