[HTML][HTML] A peripheral circulating compartment of natural naive CD4+ Tregs

D Valmori, A Merlo, NE Souleimanian… - The Journal of …, 2005 - Am Soc Clin Investig
D Valmori, A Merlo, NE Souleimanian, CS Hesdorffer, M Ayyoub
The Journal of clinical investigation, 2005Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation