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

A peripheral circulating compartment of natural naive CD4+ Tregs

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 3

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Replicative history of CD4+ T cell populations defined by the expression...
Replicative history of CD4+ T cell populations defined by the expression of CD45RA and CD25. (A) Ex vivo–sorted CD4+ T cell subsets were assessed for telomere length using telomere-specific peptide nucleic acid–fluorescent in situ hybridization (FISH) followed by flow cytometry analysis. Histograms shown are from 1 representative donor. (B) Telomere length data are shown as the mean values obtained for 3 independent donors. (C) Quantification of TREC content of ex vivo–sorted CD4+ T cell subsets. Genomic DNA of sorted subsets was isolated, and the number of TRECs was determined by quantitative real-time PCR. Data are shown as the mean values obtained for 3 independent donors. *Below detection limit.