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A peripheral circulating compartment of natural naive CD4 Tregs

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Valmori, Danila, Merlo, Andrea, Souleimanian, Naira E., Hesdorffer, Charles S., Ayyoub, Maha·2005·Journal of Clinical Investigation

DOI 10.1172/jci23963PMC PMC1159133

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Abstract

CD4CD25 Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4CD25 Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4CD25 Treg populations have been described as composed of antigen-experienced T cells that fail to significantly proliferate following TCR stimulation but suppress proliferation and effector functions of CD25 T cells. Here we show that analysis of CD25 expression in human circulating CD4 T lymphocytes with respect to their in vivo differentiation stages identifies a distinct subset of CD25CCR7CD62LCTLA-4FOXP3 cells contained in the CD45RA/RO naive fraction. The subset, which we have named natural naive Tregs (NnTregs), is prominent in young adults and decreases with age together with the total naive CD4 population. NnTregs are anergic following stimulation in the absence of IL-2 and exert ex vivo cell-cell contact-mediated suppressor functions. In addition, they proliferate in response to stimulation with autologous APCs, which indicates a high enrichment in T cells bearing self-reactive TCRs. The definition of this subset has important implications for the analysis of human naturally occurring Tregs and for their targeting in therapeutic immune interventions.

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Authors: Valmori, D., Merlo, A., Souleimanian, N. E., Hesdorffer, C. S., & Ayyoub, M.
Affiliations: Columbia University Irving Medical Center (US)
Columbia University (US)
ORCID: Merlo, Andrea
Ayyoub, Maha
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2005-07-01
Volume: 115
Issue: 7
Pages: 1953-1962
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci23963
PMC: PMC1159133
OpenAlex: W2162261192
Cited by: 319
References: 44
Citations by year: 2026: 5 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 12 · 2021: 7 · 2020: 7 · 2019: 11 · 2018: 2 · 2017: 13 · 2016: 15 · 2015: 16 · 2014: 14 · 2013: 25 · 2012: 20
FWCI: 7.92
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Cancer Research Institute
Ludwig Institute for Cancer Research
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 › Reproductive System and Pregnancy
Keywords: CD4+CD25+ Treg, Foxp3, Treg differentiation, autoreactive T cells, T cell anergy, IL-2 dependence, CCR7, CTLA-4, L-selectin, aging, antigen-experienced T cells
MeSH terms: Adult, Animals, Antigens, Differentiation, Base Sequence, Cell Separation, DNA-Binding Proteins, Flow Cytometry, Humans, Immunity, Innate, Receptors, Interleukin-2, CD4-Positive T-Lymphocytes, Antigens, CD, Gene Expression, Immunophenotyping, T-Lymphocyte Subsets, Leukocyte Common Antigens, Self Tolerance, DNA, Complementary, L-Selectin, Receptors, Chemokine, Cell Proliferation, Mice, Forkhead Transcription Factors, Receptors, CCR7, CTLA-4 Antigen, In Vitro Techniques

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A peripheral circulating compartment of natural naive CD4 Tregs

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