Heterogeneity of Natural Foxp3⁺ T Cells: A Committed Regulatory T-Cell Lineage and an Uncommitted Minor Population Retaining Plasticity

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (6), p.1903-1908
• Main Authors: Komatsu, Noriko, Mariotti-Ferrandiz, Maria Encarnita, Wang, Ying, Malissen, Bernard, Waldmann, Herman, Hori, Shohei, Bevan, Michael J.
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; B lymphocytes; Biological Sciences; Cell Differentiation; Cell division; Cell Lineage; Cytokines; Cytokines - pharmacology; Down regulation; Forkhead Transcription Factors; Forkhead Transcription Factors - analysis; Immunology; Life Sciences; Lymphocyte Subsets; Lymphocyte Subsets - cytology; Lymphocytes; Mice; Mice, Inbred C57BL; Phenotypes; Spleen cells; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Helper-Inducer - cytology; T-Lymphocytes, Regulatory; T-Lymphocytes, Regulatory - chemistry; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - transplantation; Transforming Growth Factor beta; Transforming Growth Factor beta - pharmacology; Transponders
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0811556106

Natural regulatory T cells (${\rm{T}}_{{\rm{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 ${\rm{CD4}}^ + {\rm{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 (${\rm{T}}_{\rm{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-β to maintain Foxp3 expression and responding to other cytokines by differentiating into effector ${\rm{T}}_{\rm{h}} $ in vitro. In contrast, ${\rm{CD4}}^ + {\rm{Foxp3}}^ + {\rm{CD25}}^{{\rm{high}}} $ T cells are resistant to such conversion to effector ${\rm{T}}_{\rm{h}} $ even after many rounds of cell division. These results demonstrate that natural ${\rm{Foxp3}}^ + $ T cells are a heterogeneous population consisting of a committed ${\rm{T}}_{{\rm{reg}}} $ lineage and an uncommitted subpopulation with developmental plasticity.