Foxp3+ follicular regulatory T cells control the germinal center response

Linterman, Michelle A; Pierson, Wim; Lee, Sau K; Kallies, Axel; Kawamoto, Shimpei; Rayner, Tim F; Srivastava, Monika; Divekar, Devina P; Beaton, Laura; Hogan, Jennifer J; Fagarasan, Sidonia; Liston, Adrian; Smith, Kenneth G C; Vinuesa, Carola G

doi:10.1038/nm.2425

Cited by 1,292T-cell and B-cell ImmunologyPsoriasis: Treatment and PathogenesisRenal Transplantation Outcomes and Treatments

Foxp3+ follicular regulatory T cells control the germinal center response

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Linterman, Michelle A, Pierson, Wim, Lee, Sau K, Kallies, Axel, Kawamoto, Shimpei, Rayner, Tim F, Srivastava, Monika, Divekar, Devina P +6 more·2011·Nature Medicine

DOI 10.1038/nm.2425PMC PMC3182542

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Abstract

Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.

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An increasing list of transcription factors, including IRF4, STAT3, T-bet, GATA3, Bcl-6, and Blimp-1, regulate both effector T cell function and regulatory T cell function.
“an increasing list of transcription factors now shown to regulate both effector T cell function and regulatory T cell function, including IRF4, STAT3, T-bet, GATA3, Bcl-6, and Blimp-1 [98–105].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [102]

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Authors: Linterman, M. A., Pierson, W., Lee, S. K., Kallies, A., Kawamoto, S., Rayner, T. F., Srivastava, M., Divekar, D. P., Beaton, L., Hogan, J. J., Fagarasan, S., Liston, A., Smith, K. G. C., & Vinuesa, C. G.
Affiliations: University of Cambridge (GB)
Vlaams Instituut voor Biotechnologie (BE)
Australian National University (AU)
Walter and Eliza Hall Institute of Medical Research (AU)
RIKEN (JP)
Corresponding author: Liston, Adrian
Smith, Kenneth G C
Vinuesa, Carola G
ORCID: Linterman, Michelle A
Pierson, Wim
Kallies, Axel
Kawamoto, Shimpei
Rayner, Tim F
Srivastava, Monika
Beaton, Laura
Fagarasan, Sidonia
Liston, Adrian
Smith, Kenneth G C
Vinuesa, Carola G
Venue: Nature Medicine
Publisher: Springer Science and Business Media LLC
Published: 2011-07-24
Volume: 17
Issue: 8
Pages: 975-982
ISSN: 1078-8956 (ISSN-L)
1546-170X
DOI: 10.1038/nm.2425
PMC: PMC3182542
OpenAlex: W2060637301
Cited by: 1,292
References: 54
Citations by year: 2026: 50 · 2025: 49 · 2024: 69 · 2023: 77 · 2022: 89 · 2021: 124 · 2020: 98 · 2019: 109 · 2018: 109 · 2017: 97 · 2016: 78 · 2015: 96 · 2014: 90 · 2013: 74 · 2012: 67
FWCI: 34.75
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Medicine (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
QUT ePrints (Queensland University of Technology) (submittedVersion)
Minerva Access (University of Melbourne) (submittedVersion)
ANU Open Research (Australian National University) (submittedVersion)
Funders: Wellcome Trust (083650/Z/07/Z, 083650)
Topics: Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
Keywords: follicular regulatory T cells, Foxp3+ regulatory T cells, T follicular helper cells, germinal center, B cell tolerance, somatic hypermutation, affinity maturation, BCL6, SAP, CD28, antigen-specific B cells, self-tolerance
MeSH terms: Positive Regulatory Domain I-Binding Factor 1, Animals, B-Lymphocytes, Cell Differentiation, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Immunohistochemistry, Membrane Proteins, Mice, Inbred C57BL, Repressor Proteins, Self Tolerance, Mice, Knockout, Statistics, Nonparametric, Germinal Center, T-Lymphocytes, Regulatory, Mice, Proto-Oncogene Proteins c-bcl-6, Forkhead Transcription Factors, Receptors, CXCR5

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Foxp3+ follicular regulatory T cells control the germinal center response

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