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.
Komatsu
Noriko
N
Research Unit for Immune Homeostasis, RIKEN Research Center for Allergy and Immunology, Yokohama 230-0045, Japan.
Mariotti-Ferrandiz
Maria Encarnita
ME
Wang
Ying
Y
Malissen
Bernard
B
Waldmann
Herman
H
Hori
Shohei
S
D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D016207:Cytokines / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000032:analysis*; D016131:Lymphocyte Subsets / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000166:cytology* / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta