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A peripheral circulating compartment of natural naive CD4+ Tregs
Danila Valmori, … , Charles S. Hesdorffer, Maha Ayyoub
Danila Valmori, … , Charles S. Hesdorffer, Maha Ayyoub
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1953-1962. https://doi.org/10.1172/JCI23963.
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Research Article Immunology Article has an altmetric score of 3

A peripheral circulating compartment of natural naive CD4+ Tregs

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Abstract

CD4+CD25+ Tregs play a central role in the maintenance of peripheral self tolerance by keeping autoreactive T cells in check. Whereas the thymic origin of CD4+CD25+ Tregs, as a distinct lineage, has been inferred, understanding of their developmental pathways has remained elusive. In both mice and humans, peripheral CD4+CD25+ 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 CD25+CCR7+CD62L+CTLA-4+FOXP3+ 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.

Authors

Danila Valmori, Andrea Merlo, Naira E. Souleimanian, Charles S. Hesdorffer, Maha Ayyoub

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Figure 1

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Expression of CD25 and CD45RA defines 4 distinct subsets of peripheral b...
Expression of CD25 and CD45RA defines 4 distinct subsets of peripheral blood CD4+ T cells. Peripheral blood lymphocytes were stained with monoclonal antibodies to CD3, CD4, CD25, and CD45RA, which identified 4 major subsets. (A) Gated on lymphocytes. (B) Gated on CD4+ T cells. (C) CD4+ T cell subsets were further analyzed for the expression of CD45RO, CCR7, CD62L, and CTLA-4. Numbers indicate percentages of CCR7- or CD62L-expressing cells. (D) FOXP3 gene expression was assessed by conventional and by quantitative real-time PCR on the corresponding 4 sorted populations. For the PCR, an example from a representative donor is shown. Δ Rn is the difference between the Rn (emission intensity of the reporter dye/emission intensity of the passive reference) of the sample (PCR reaction with cDNA template) and the Rn of a control (PCR reaction without cDNA template or early cycles of a real-time reaction). Real-time PCR data are shown as the mean values obtained from 3 independent donors.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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