Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

Miyara, Makoto; Yoshioka, Yumiko; Kitoh, Akihiko; Shima, Tomoko; Wing, Kajsa; Niwa, Akira; Parizot, Christophe; Taflin, Cécile; Heike, Toshio; Valeyre, Dominique; Mathian, Alexis; Nakahata, Tatsutoshi; Yamaguchi, Tomoyuki; Nomura, Takashi; Ono, Masahiro; Amoura, Zahir; Gorochov, Guy; Sakaguchi, Shimon

doi:10.1016/j.immuni.2009.03.019

Cited by 2,291T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisFOXO transcription factor regulation

Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

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Miyara, Makoto, Yoshioka, Yumiko, Kitoh, Akihiko, Shima, Tomoko, Wing, Kajsa, Niwa, Akira, Parizot, Christophe, Taflin, Cécile +10 more·2009·Immunity

DOI 10.1016/j.immuni.2009.03.019

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Abstract

FoxP3 is a key transcription factor for the development and function of natural CD4(+) regulatory T cells (Treg cells). Here we show that human FoxP3(+)CD4(+) T cells were composed of three phenotypically and functionally distinct subpopulations: CD45RA(+)FoxP3(lo) resting Treg cells (rTreg cells) and CD45RA(-)FoxP3(hi) activated Treg cells (aTreg cells), both of which were suppressive in vitro, and cytokine-secreting CD45RA(-)FoxP3(lo) nonsuppressive T cells. The proportion of the three subpopulations differed between cord blood, aged individuals, and patients with immunological diseases. Terminally differentiated aTreg cells rapidly died whereas rTreg cells proliferated and converted into aTreg cells in vitro and in vivo. This was shown by the transfer of rTreg cells into NOD-scid-common gamma-chain-deficient mice and by TCR sequence-based T cell clonotype tracing in peripheral blood in a normal individual. Taken together, the dissection of FoxP3(+) cells into subsets enables one to analyze Treg cell differentiation dynamics and interactions in normal and disease states, and to control immune responses through manipulating particular FoxP3(+) subpopulations.

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Even within Tregs the intensity of FOXP3 expression can change, with naive or resting populations of Tregs expressing lower levels of FOXP3 than activated Tregs.
“Moreover, even within Tregs the intensity of FOXP3 expression can change, with naive or resting populations of Tregs expressing lower levels of FOXP3 than activated Tregs [379, 380].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [379]
FoxP3 is also transiently expressed on effector T cells and tumor cells in humans.
“FoxP3 is also transiently expressed on effector T cells and tumor cells in humans [165].”
From Potential anti-tumor effects of regulatory T cells in the tumor microenvironment: a review (2024) · cites this paper as [165]

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Authors: Miyara, M., Yoshioka, Y., Kitoh, A., Shima, T., Wing, K., Niwa, A., Parizot, C., Taflin, C., Heike, T., Valeyre, D., Mathian, A., Nakahata, T., Yamaguchi, T., Nomura, T., Ono, M., Amoura, Z., Gorochov, G., & Sakaguchi, S.
Affiliations: Kyoto University (JP)
Inserm (FR)
Assistance Publique – Hôpitaux de Paris (FR)
Corresponding author: Sakaguchi, Shimon
ORCID: Miyara, Makoto
Yoshioka, Yumiko
Kitoh, Akihiko
Wing, Kajsa
Niwa, Akira
Parizot, Christophe
Taflin, Cécile
Valeyre, Dominique
Mathian, Alexis
Nakahata, Tatsutoshi
Yamaguchi, Tomoyuki
Nomura, Takashi
Ono, Masahiro
Amoura, Zahir
Gorochov, Guy
Sakaguchi, Shimon
Venue: Immunity
Publisher: Elsevier BV
Published: 2009-06
Volume: 30
Issue: 6
Pages: 899-911
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2009.03.019
OpenAlex: W2007631222
Cited by: 2,291
References: 50
Citations by year: 2026: 69 · 2025: 97 · 2024: 135 · 2023: 107 · 2022: 164 · 2021: 170 · 2020: 171 · 2019: 173 · 2018: 160 · 2017: 135 · 2016: 160 · 2015: 132 · 2014: 134 · 2013: 134 · 2012: 126
FWCI: 49.47
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1538 d)
Locations: Immunity (publishedVersion)
PubMed (publishedVersion)
UCL Discovery (University College London) (submittedVersion)
Funders: European Commission
Japan Society for the Promotion of Science (21791073)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
Keywords: Foxp3, regulatory T cells, CD4+ T cells, Treg differentiation, CD45RA, Treg cell proliferation, immune disorders, aging, umbilical cord blood, immune tolerance
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, Cell Differentiation, T-Lymphocytes, Helper-Inducer, Humans, CD4-Positive T-Lymphocytes, Leukocyte Common Antigens, T-Lymphocytes, Regulatory, Forkhead Transcription Factors, Interleukin-2 Receptor alpha Subunit, Young Adult

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Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor

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