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Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity.

Natural regulatory T cells (T(reg)) represent a distinct lineage of T lymphocytes committed to suppressive functions, and expression of the transcription factor Foxp3 is thought to identify this lineage specifically. Here we report that, whereas the majority of natural CD4(+)Foxp3(+) T cells maintain stable Foxp3 expression after adoptive transfer to lymphopenic or lymphoreplete recipients, a minor fraction enriched within the CD25(-) subset actually lose it. Some of those Foxp3(-) T cells adopt effector helper T cell (T(h)) functions, whereas some retain "memory" of previous Foxp3 expression, reacquiring Foxp3 upon activation. This minority "unstable" population exhibits flexible responses to cytokine signals, relying on transforming growth factor-beta to maintain Foxp3 expression and responding to other cytokines by differentiating into effector T(h) in vitro. In contrast, CD4(+)Foxp3(+)CD25(high) T cells are resistant to such conversion to effector T(h) even after many rounds of cell division. These results demonstrate that natural Foxp3(+) T cells are a heterogeneous population consisting of a committed T(reg) lineage and an uncommitted subpopulation with developmental plasticity.

Pubmed ID: 19174509


  • Komatsu N
  • Mariotti-Ferrandiz ME
  • Wang Y
  • Malissen B
  • Waldmann H
  • Hori S


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

February 10, 2009

Associated Grants

  • Agency: Medical Research Council, Id: G7904009
  • Agency: Medical Research Council, Id:

Mesh Terms

  • Adoptive Transfer
  • Animals
  • Cell Differentiation
  • Cell Lineage
  • Cytokines
  • Forkhead Transcription Factors
  • Lymphocyte Subsets
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes, Helper-Inducer
  • T-Lymphocytes, Regulatory
  • Transforming Growth Factor beta