Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions
Open accessAbstract
Foxp3(+) regulatory T (T(reg)) cells suppress different types of immune responses to help maintain homeostasis in the body. How T(reg) cells regulate humoral immunity, including germinal center reactions, is unclear. Here we identify a subset of T(reg) cells expressing CXCR5 and Bcl-6 that localize to the germinal centers in mice and humans. The expression of CXCR5 on T(reg) cells depends on Bcl-6. These CXCR5(+)Bcl-6(+) T(reg) cells are absent in the thymus but can be generated de novo from CXCR5(-)Foxp3(+) natural T(reg) precursors. A lack of CXCR5(+) T(reg) cells leads to greater germinal center reactions including germinal center B cells, affinity maturation of antibodies and the differentiation of plasma cells. These results unveil a Bcl-6-CXCR5 axis in T(reg) cells that drives the development of follicular regulatory T (T(FR)) cells that function to inhibit the germinal center reactions.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [101]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Doreau, A., Bélot, A., Bastid, J., Riche, B., Trescol-Biémont, M.-C., Ranchin, B., Fabien, N., Cochat, P., Pouteil‐Noble, C., Trolliet, P., et al. (2009) · Nature Immunology · doi:10.1038/ni.1741 · Cited by 448 · see citing works
RetractedControl of Regulatory T Cell Development by the Transcription Factor <i>Foxp3</i>
Hori, S., Nomura, T., & Sakaguchi, S. (2003) · Science · doi:10.1126/science.1079490 · Cited by 8,187 · see citing works
Foxp3 programs the development and function of CD4+CD25+ regulatory T cells
Fontenot, J. D., Gavin, M. A., & Rudensky, A. Y. (2003) · Nature Immunology · doi:10.1038/ni904 · Cited by 7,745 · see citing works
A Novel Transcription Factor, T-bet, Directs Th1 Lineage Commitment
Szabo, S. J., Kim, S. T., Costa, G. L., Zhang, X., Fathman, C. G., & Glimcher, L. H. (2000) · Cell · doi:10.1016/s0092-8674(00)80702-3 · Cited by 3,589 · see citing works
Johnston, R. J., Poholek, A. C., DiToro, D., Yusuf, I., Eto, D., Barnett, B., Dent, A. L., Craft, J., & Crotty, S. (2009) · Science · doi:10.1126/science.1175870 · Cited by 1,626 · see citing works
Bcl6 mediates the development of T follicular helper cells
Nurieva, R. I., Chung, Y., Martinez, G. J., Yang, X. O., Tanaka, S., Matskevitch, T. D., Wang, Y.-H., & Dong, C. (2009) · Science · doi:10.1126/science.1176676 · Cited by 1,506 · see citing works
Self-citationSTAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells
Yang, X. O., Panopoulos, A. D., Nurieva, R., Chang, S. H., Wang, D., Watowich, S. S., & Dong, C. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.c600321200 · Cited by 1,494 · see citing works
Self-citationBreitfeld, D., Ohl, L., Kremmer, E., Ellwart, J., Sallusto, F., Lipp, M., & Förster, R. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.11.1545 · Cited by 1,464 · see citing works
Thornton, A. M., Korty, P. E., Tran, D. Q., Wohlfert, E. A., Murray, P. E., Belkaid, Y., & Shevach, E. M. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0904028 · Cited by 1,382 · see citing works
Cxc Chemokine Receptor 5 Expression Defines Follicular Homing T Cells with B Cell Helper Function
Schaerli, P., Willimann, K., Lang, A. B., Lipp, M., Loetscher, P., & Moser, B. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.11.1553 · Cited by 1,263 · see citing works
Koch, M. A., Tucker-Heard, G., Perdue, N. R., Killebrew, J. R., Urdahl, K. B., & Campbell, D. J. (2009) · Nature Immunology · doi:10.1038/ni.1731 · Cited by 1,258 · see citing works
The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage Commitment
Yu, D., Rao, S., Tsai, L. M., Lee, S. K., He, Y., Sutcliffe, E. L., Srivastava, M., Linterman, M. A., Zheng, L., Simpson, N., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.07.002 · Cited by 1,216 · see citing works
Nurieva, R. I., Chung, Y., Hwang, D., Yang, X. O., Kang, H. S., Ma, L., Wang, Y.-H., Watowich, S. S., Jetten, A. M., Tian, Q., et al. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.009 · Cited by 1,205 · see citing works
Self-citationHori, S., Nomura, T., & Sakaguchi, S. (2017) · The Journal of Immunology · doi:10.1093/jimmunol/198.3.981 · Cited by 1,067 · see citing works
CD4 <sup>+</sup> Regulatory T Cells Control T <sub>H</sub> 17 Responses in a Stat3-Dependent Manner
Chaudhry, A., Rudra, D., Treuting, P., Samstein, R. M., Liang, Y., Kas, A., & Rudensky, A. Y. (2009) · Science · doi:10.1126/science.1172702 · Cited by 1,000 · see citing works
Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses
Zheng, Y., Chaudhry, A., Kas, A., deRoos, P., Kim, J. M., Chu, T.-T., Corcoran, L., Treuting, P., Klein, U., & Rudensky, A. Y. (2009) · Nature · doi:10.1038/nature07674 · Cited by 958 · see citing works
The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation
Ye, B. H., Cattoretti, G., Shen, Q. “., Zhang, J., Hawe, N., de Waard, R., Leung, C. C., Nouri-Shirazi, M. A., Orazi, A., Chaganti, R. S. K., et al. (1997) · Nature Genetics · doi:10.1038/ng0697-161 · Cited by 820 · see citing works
Cytokine-secreting follicular T cells shape the antibody repertoire
Reinhardt, R. L., Liang, H.-E., & Locksley, R. M. (2009) · Nature Immunology · doi:10.1038/ni.1715 · Cited by 807 · see citing works
A Fundamental Role for Interleukin-21 in the Generation of T Follicular Helper Cells
Vogelzang, A., McGuire, H. M., Yu, D., Sprent, J., Mackay, C. R., & King, C. (2008) · Immunity · doi:10.1016/j.immuni.2008.06.001 · Cited by 738 · see citing works
Stability of the Regulatory T Cell Lineage in Vivo
Rubtsov, Y. P., Niec, R. E., Josefowicz, S., Li, L., Darce, J., Mathis, D., Benoist, C., & Rudensky, A. Y. (2010) · Science · doi:10.1126/science.1191996 · Cited by 730 · see citing works
Hsu, H., Yang, P., Wang, J., Wu, Q., Myers, R. C., Chen, J., Yi, J. S., Guentert, T., Tousson, A., Stanus, A. L., et al. (2007) · Nature Immunology · doi:10.1038/ni1552 · Cited by 717 · see citing works
Bauquet, A. T., Jin, H., Paterson, A. M., Mitsdoerffer, M., Ho, I.-C., Sharpe, A. H., & Kuchroo, V. K. (2009) · Nature Immunology · doi:10.1038/ni.1690 · Cited by 713 · see citing works
Subspecialization of Cxcr5+ T Cells
Kim, C. H., Rott, L. S., Clark‐Lewis, I., Campbell, D., Wu, L., & Butcher, E. C. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.12.1373 · Cited by 621 · see citing works
Cretney, E., Xin, A., Shi, W., Minnich, M., Masson, F., Miasari, M., Belz, G. T., Smyth, G. K., Busslinger, M., Nutt, S. L., et al. (2011) · Nature Immunology · doi:10.1038/ni.2006 · Cited by 605 · see citing works
Preferential Generation of Follicular B Helper T Cells from Foxp3 + T Cells in Gut Peyer's Patches
Tsuji, M., Komatsu, N., Kawamoto, S., Suzuki, K., Kanagawa, O., Honjo, T., Hori, S., & Fagarasan, S. (2009) · Science · doi:10.1126/science.1169152 · Cited by 592 · see citing works
Proinflammatory T helper type 17 cells are effective B-cell helpers
Mitsdoerffer, M., Lee, Y., Jäger, A., Kim, H.-J., Korn, T., Kolls, J. K., Cantor, H., Bettelli, E., & Kuchroo, V. K. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1009234107 · Cited by 534 · see citing works
Dysregulation of germinal centres in autoimmune disease
Vinuesa, C. G., Sanz, I., & Cook, M. (2009) · Nature reviews. Immunology · doi:10.1038/nri2637 · Cited by 465 · see citing works
Ise, W., Kohyama, M., Schraml, B. U., Zhang, T., Schwer, B., Basu, U., Alt, F. W., Tang, J., Oltz, E. M., Murphy, T. L., et al. (2011) · Nature Immunology · doi:10.1038/ni.2037 · Cited by 377 · see citing works
Sugimoto, N., Oida, T., Hirota, K., Nakamura, K., Nomura, T., Uchiyama, T., & Sakaguchi, S. (2006) · International Immunology · doi:10.1093/intimm/dxl060 · Cited by 366 · see citing works
Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance
Kim, H., Verbinnen, B., Tang, X., Lu, L., & Cantor, H. (2010) · Nature · doi:10.1038/nature09370 · Cited by 362 · see citing works
Rengarajan, J., Mowen, K. A., McBride, K. D., Smith, E. D., Singh, H., & Glimcher, L. H. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011128 · Cited by 332 · see citing works
B‐lymphocyte contributions to human autoimmune disease
Yanaba, K., Bouaziz, J., Matsushita, T., MAGRO, C. M. J., Clair, E. W. S., & Tedder, T. F. (2008) · Immunological Reviews · doi:10.1111/j.1600-065x.2008.00646.x · Cited by 327 · see citing works
Lim, H. W., Hillsamer, P., & Kim, C. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci22325 · Cited by 288 · see citing works
Self-citationLim, H. W., Hillsamer, P., & Kim, C. H. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422325 · Cited by 260 · see citing works
Self-citationDysregulated T helper cell differentiation in the absence of interferon regulatory factor 4
Lohoff, M. D., Mittrücker, H., Prechtl, S., Bischof, S., Sommer, F. O., Kock, S., Ferrick, D. A., Duncan, G. S., Gessner, A., & Mak, T. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182425099 · Cited by 253 · see citing works
New insights into the differentiation and function of T follicular helper cells
King, C. (2009) · Nature reviews. Immunology · doi:10.1038/nri2644 · Cited by 215 · see citing works
FOXP3 acts as a rheostat of the immune response
Ochs, H. D., Ziegler, S. F., & Torgerson, T. R. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00231.x · Cited by 203 · see citing works
Ono, M., Shimizu, J., Miyachi, Y., & Sakaguchi, S. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.8.4748 · Cited by 162 · cited 5× · see citing works
“1 + congenic mice were isolated by using FACS Aria ® (BD Bioscience) 36 .”
Influential
Flagged first, then by citations
Cited by
Sorted by citations
Regulatory T cells: mechanisms of differentiation and function
Josefowicz, S. Z., Lu, L.-F., & Rudensky, A. Y. (2012) · Annual Review of Immunology · doi:10.1146/annurev.immunol.25.022106.141623 · Cited by 2,866 · see citing works
T follicular helper cell differentiation, function, and roles in disease
Crotty, S. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.004 · Cited by 1,847 · see citing works
Victora, G. D., & Nussenzweig, M. C. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-075032 · Cited by 1,878 · see citing works
Gut Microbial Metabolites Fuel Host Antibody Responses
Kim, M., Qie, Y., Park, J., & Kim, C. H. (2016) · Cell Host & Microbe · doi:10.1016/j.chom.2016.07.001 · Cited by 893 · see citing works
Human FOXP3+ Regulatory T Cell Heterogeneity and Function in Autoimmunity and Cancer
Wing, J. B., Tanaka, A., & Sakaguchi, S. (2019) · Immunity · doi:10.1016/j.immuni.2019.01.020 · Cited by 726 · see citing works
Biology and regulation of IL-2: from molecular mechanisms to human therapy
Spolski, R., Li, P., & Leonard, W. J. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0046-y · Cited by 637 · see citing works
Development and maintenance of intestinal regulatory T cells
Tanoue, T., Atarashi, K., & Honda, K. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2016.36 · Cited by 553 · see citing works
Clambey, E. T., McNamee, E. N., Westrich, J. A., Glover, L. E., Campbell, E. L., Jedlicka, P., de Zoeten, E. F., Cambier, J. C., Stenmark, K. R., Colgan, S. P., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1202366109 · Cited by 560 · see citing works
Kawamoto, S., Maruya, M., Kato, L. M., Suda, W., Atarashi, K., Doi, Y., Tsutsui, Y., Qin, H., Honda, K., Okada, T., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.05.016 · Cited by 531 · see citing works
Hirota, K., Turner, J.-E., Villa, M., Duarte, J. H., Demengeot, J., Steinmetz, O. M., & Stockinger, B. (2013) · Nature Immunology · doi:10.1038/ni.2552 · Cited by 509 · see citing works
Saravia, J., Chapman, N. M., & Chi, H. (2019) · Cellular & Molecular Immunology · doi:10.1038/s41423-019-0220-6 · Cited by 489 · see citing works
Single-cell gene expression reveals a landscape of regulatory T cell phenotypes shaped by the TCR
Zemmour, D., Zilionis, R., Kiner, E., Klein, A. M., Mathis, D., & Benoist, C. (2018) · Nature Immunology · doi:10.1038/s41590-018-0051-0 · Cited by 384 · see citing works
Regulation of the Germinal Center Response
Stebegg, M., Kumar, S. D., Silva-Cayetano, A., Fonseca, V. R., Linterman, M. A., & Graca, L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02469 · Cited by 349 · see citing works
Intestinal IgA production and its role in host-microbe interaction
Gutzeit, C., Magri, G., & Cerutti, A. (2014) · Immunological Reviews · doi:10.1111/imr.12189 · Cited by 332 · see citing works
McNamee, E. N., Korns Johnson, D., Homann, D., & Clambey, E. T. (2013) · Immunologic Research · doi:10.1007/s12026-012-8349-8 · Cited by 234 · see citing works
Wing, J. B., Kitagawa, Y., Locci, M., Hume, H., Tay, C., Morita, T., Kidani, Y., Matsuda, K., Inoue, T., Kurosaki, T., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1705551114 · Cited by 211 · see citing works
Takahashi, D., Hoshina, N., Kabumoto, Y., Maeda, Y., Suzuki, A., Tanabe, H., Isobe, J., Yamada, T., Muroi, K., Yanagisawa, Y., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.102913 · Cited by 205 · see citing works
Proietti, M., Cornacchione, V., Rezzonico Jost, T., Romagnani, A., Faliti, C. E., Perruzza, L., Rigoni, R., Radaelli, E., Caprioli, F., Preziuso, S., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.010 · Cited by 181 · see citing works
Control of inflammation by integration of environmental cues by regulatory T cells
Chaudhry, A., & Rudensky, A. Y. (2013) · Journal of Clinical Investigation · doi:10.1172/jci57175 · Cited by 183 · see citing works
Fang, D., & Zhu, J. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20170494 · Cited by 175 · see citing works
Helios Controls a Limited Subset of Regulatory T Cell Functions
Sebastian, M., Lopez-Ocasio, M., Metidji, A., Rieder, S. A., Shevach, E. M., & Thornton, A. M. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501704 · Cited by 172 · see citing works
Generation of RORγt+ Antigen-Specific T Regulatory 17 Cells from Foxp3+ Precursors in Autoimmunity
Kim, B.-S., Lu, H., Ichiyama, K., Chen, X., Zhang, Y.-B., Mistry, N. A., Tanaka, K., Lee, Y.-H., Nurieva, R., Zhang, L., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.021 · Cited by 137 · see citing works
Self-citationBarnett, L. G., Simkins, H. M. A., Barnett, B. E., Korn, L. L., Johnson, A. L., Wherry, E. J., Wu, G. F., & Laufer, T. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301284 · Cited by 123 · see citing works
Green, M. R., Vicente-Dueñas, C., Romero-Camarero, I., Long Liu, C., Dai, B., González-Herrero, I., García-Ramírez, I., Alonso-Escudero, E., Iqbal, J., Chan, W. C., et al. (2014) · Nature Communications · doi:10.1038/ncomms4904 · Cited by 88 · see citing works
Human T follicular helper clones seed the germinal center-resident regulatory pool
Le Coz, C., Oldridge, D. A., Herati, R. S., De Luna, N., Garifallou, J., Cruz Cabrera, E., Belman, J. P., Pueschl, D., Silva, L. V., Knox, A. V. C., et al. (2023) · Science Immunology · doi:10.1126/sciimmunol.ade8162 · Cited by 77 · see citing works
How T follicular helper cells and the germinal centre response change with age
Linterman, M. A. (2014) · Immunology & Cell Biology · doi:10.1038/icb.2013.77 · Cited by 69 · see citing works
- Authors
- Chung, Y., Tanaka, S., Chu, F., Nurieva, R. I., Martinez, G. J., Rawal, S., Wang, Y.-H., Lim, H., Reynolds, J. M., Zhou, X.-H., Fan, H.-M., Liu, Z.-M., Neelapu, S. S., & Dong, C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
- Corresponding author
- Chung, Yeonseok
- Dong, Chen
- ORCID
- Venue
- Nature Medicine
- Published
- 2011-07-24
- Volume
- 17
- Issue
- 8
- Pages
- 983-988
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3151340
- OpenAlex
- W2063223775
- Cited by
- 1,120
- References
- 38
- Citations by year
- 2026: 38 · 2025: 43 · 2024: 64 · 2023: 73 · 2022: 72 · 2021: 98 · 2020: 81 · 2019: 99 · 2018: 96 · 2017: 78 · 2016: 78 · 2015: 71 · 2014: 93 · 2013: 65 · 2012: 56
- FWCI
- 32.22
- 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)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI083761)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (RC2AR059010, R01AR050772)
- 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, BCL6, CXCR5, germinal center, T follicular helper cells, humoral immunity, affinity maturation, plasma cell differentiation, natural regulatory T cells, immune tolerance
- MeSH terms
- Animals, B-Lymphocytes, Cell Differentiation, DNA-Binding Proteins, Humans, Immunohistochemistry, Mice, Inbred C57BL, Palatine Tonsil, Self Tolerance, Mice, Knockout, Germinal Center, Adoptive Transfer, T-Lymphocytes, Regulatory, Mice, Proto-Oncogene Proteins c-bcl-6, Forkhead Transcription Factors, Receptors, CXCR5
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
