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 4

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Proliferation, cytokine production, and suppressor functions of NnTregs....
Proliferation, cytokine production, and suppressor functions of NnTregs. (A) NnTregs and other CD4+ T cell subsets were isolated by FACS cell sorting and stimulated with plate-bound anti-CD3/CD28 antibodies in the presence of APCs. Cell proliferation was assessed on day 7 after stimulation. Results of duplicate cultures are shown for 2 independent donors. (B) T cell subsets were stimulated by PMA/ionomycin. The concentration of cytokines in the culture supernatants was assessed by ELISA 24 hours after stimulation. Results of duplicate cultures are shown for 2 independent donors. No detectable cytokines were produced by any of the populations in the absence of stimulation (data not shown). (C) Ex vivo–sorted NnTreg and Treg populations were cocultured with responders (CFSE-labeled CD4+CD25– T cells) in the presence of PHA at the indicated suppressor/responder cell ratio. As internal control, CFSE-responders were cocultured with unlabeled responders or with the indicated suppressor population in transwell plates. The growth of CSFE-labeled responders was assessed by flow cytometry at day 5 after stimulation. Results are shown as mean values from 3 independent donors.