Single-Cell Analysis of the Human T Regulatory Population Uncovers Functional Heterogeneity and Instability within FOXP3+ Cells
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Natural FOXP3+CD4+CD25High regulatory T cells are critical in immunological self-tolerance. Their characterization in humans is hindered by the failure to discriminate these cells from activated effector T cells in inflammation. To explore the relationship between FOXP3 expression and regulatory function at the clonal level, we used a single-cell cloning strategy of CD25-expressing CD4+ T cell subsets from healthy human donors. Our approach unveils a functional heterogeneity nested within CD4+CD25HighFOXP3+ T cells, and typically not revealed by conventional bulk assays. Whereas most cells display the canonical regulatory T (Treg) cell characteristics, a significant proportion of FOXP3+ T cells is compromised in its suppressive function, despite the maintenance of other phenotypic and functional regulatory T hallmark features. In addition, these nonsuppressive FOXP3+ T cells preferentially emerge from the CD45RO+ memory pool, and arise as a consequence of a rapid downregulation of FOXP3 expression upon T cell reactivation. Surprisingly, these dysfunctional Treg cells with unstable FOXP3 expression do not manifest overt plasticity in terms of inflammatory cytokine secretion. These results open a path to an extensive study of the functional heterogeneity of CD4+CD25HighFOXP3+ Treg cells and warrant caution in the sole use of FOXP3 as a clinical marker for monitoring of immune regulation in humans.
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The strong activation and expansion of Treg cells during the rejection episode suggests engagement of strong immunosuppression in response to inflammation.
“A strong activation and expansion of Treg cells, with higher expression of Foxp3, was evident during the rejection episode, suggesting the engagement of strong immunosuppression in response to inflammation42.”
From Targeting the mTOR pathway uncouples the efficacy and toxicity of PD-1 blockade in renal transplantation (2019) · cites this paper as [42]
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Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., Evdemon-Hogan, M., Conejo-Garcia, J. R., Zhang, L., Burow, M., et al. (2004) · Nature Medicine · doi:10.1038/nm1093 · Cited by 5,151 · see citing works
Chen, W., Jin, W., Hardegen, N. J., Lei, K.-J., Li, L., Marinos, N. J., McGrady, G., & Wahl, S. M. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030152 · Cited by 4,678 · see citing works
Thornton, A. M., & Shevach, E. M. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.2.287 · Cited by 2,637 · see citing works
CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells
Liu, W., Putnam, A. L., Xu-yu, Z., Szot, G. L., Lee, M. R., Zhu, S., Gottlieb, P. A., Kapranov, P., Gingeras, T. R., de St. Groth, B. F., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060772 · Cited by 2,606 · see citing works
FOXP3+ regulatory T cells in the human immune system
Sakaguchi, S., Miyara, M., Costantino, C. M., & Hafler, D. A. (2010) · Nature reviews. Immunology · doi:10.1038/nri2785 · Cited by 2,443 · see citing works
Toll Pathway-Dependent Blockade of CD4+CD25+ T Cell-Mediated Suppression by Dendritic Cells
Pasare, C., & Medzhitov, R. (2003) · Science · doi:10.1126/science.1078231 · Cited by 2,327 · see citing works
Miyara, M., Yoshioka, Y., Kitoh, A., Shima, T., Wing, K., Niwa, A., Parizot, C., Taflin, C., Heike, T., Valeyre, D., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.03.019 · Cited by 2,291 · see citing works
Wildin, R. S., Ramsdell, F., Peake, J., Faravelli, F., Casanova, J., Buist, N. R. M., Levy‐Lahad, E., Mazzella, M., Goulet, O., Perroni, L., et al. (2001) · Nature Genetics · doi:10.1038/83707 · Cited by 1,916 · see citing works
CD4+CD25high Regulatory Cells in Human Peripheral Blood
Baecher‐Allan, C., Brown, J. A., Freeman, G. J., & Hafler, D. A. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.3.1245 · Cited by 1,857 · see citing works
Seddiki, N., Santner-Nanan, B., Martinson, J., Zaunders, J., Sasson, S., Landay, A., Solomon, M., Selby, W., Alexander, S. I., Nanan, R., et al. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20060468 · Cited by 1,512 · see citing works
Zhou, X., Bailey-Bucktrout, S. L., Jeker, L. T., Peñaranda, C., Martínez‐Llordella, M., Ashby, M., Nakayama, M., Rosenthal, W. L., & Bluestone, J. A. (2009) · Nature Immunology · doi:10.1038/ni.1774 · Cited by 1,374 · see citing works
Regulatory T cells in transplantation tolerance
Wood, K. J., & Sakaguchi, S. (2003) · Nature reviews. Immunology · doi:10.1038/nri1027 · Cited by 1,318 · see citing works
A new member of the immunoglobulin superfamily—CTLA-4
Brunet, J., Denizot, F., Luciani, M., Roux-Rouquié, M., Suzan, M., Mattéi, M., & Golstein, P. (1987) · Nature · doi:10.1038/328267a0 · Cited by 1,307 · see citing works
FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT
Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A. D., Stroud, J. C., Bates, D. L., Guo, L., Han, A., Ziegler, S. F., et al. (2006) · Cell · doi:10.1016/j.cell.2006.05.042 · Cited by 1,188 · see citing works
Interleukin‐10‐secreting type 1 regulatory T cells in rodents and humans
Roncarolo, M. G., Gregori, S., Battaglia, M., Bacchetta, R., Fleischhauer, K., & Levings, M. K. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00420.x · Cited by 1,174 · see citing works
Natural regulatory T cells in infectious disease
Belkaid, Y., & Rouse, B. T. (2005) · Nature Immunology · doi:10.1038/ni1181 · Cited by 1,036 · see citing works
Allan, S. E., Crome, S. Q., Crellin, N. K., Passerini, L., Steiner, T. S., Bacchetta, R., Roncarolo, M. G., & Levings, M. K. (2007) · International Immunology · doi:10.1093/intimm/dxm014 · Cited by 872 · see citing works
Induction and mechanism of action of transforming growth factor‐β‐secreting Th3 regulatory cells
Weiner, H. L. (2001) · Immunological Reviews · doi:10.1034/j.1600-065x.2001.1820117.x · Cited by 850 · see citing works
Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells
Zheng, Y., Josefowicz, S. Z., Kas, A., Chu, T.-T., Gavin, M. A., & Rudensky, A. Y. (2007) · Nature · doi:10.1038/nature05563 · Cited by 835 · see citing works
Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation
Korn, T., Reddy, J., Gao, W., Bettelli, E., Awasthi, A., Petersen, T. R., Bäckström, B. T., Sobel, R. A., Wucherpfennig, K. W., Strom, T. B., et al. (2007) · Nature Medicine · doi:10.1038/nm1564 · Cited by 803 · see citing works
Crucial role of FOXP3 in the development and function of human CD25+CD4+ regulatory T cells
Yagi, H., Nomura, T., Nakamura, K., Yamazaki, S., Kitawaki, T., Hori, S., Maeda, M., Onodera, M., Uchiyama, T., Fujii, S., et al. (2004) · International Immunology · doi:10.1093/intimm/dxh165 · Cited by 797 · see citing works
DNA methylation controls Foxp3 gene expression
Polansky, J. K., Kretschmer, K., Freyer, J., Floess, S., Garbe, A. I., Baron, U., Olek, S., Hamann, A., von Boehmer, H., & Huehn, J. (2008) · European Journal of Immunology · doi:10.1002/eji.200838105 · Cited by 784 · see citing works
The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells
Haxhinasto, S. A., Mathis, D. J., & Benoist, C. O. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071477 · Cited by 735 · see citing works
Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1
Ono, M., Yaguchi, H., Ohkura, N., Kitabayashi, I., Nagamura, Y., Nomura, T., Miyachi, Y., Tsukada, T., & Sakaguchi, S. (2007) · Nature · doi:10.1038/nature05673 · Cited by 683 · see citing works
Hill, J., Feuerer, M., Tash, K., Haxhinasto, S., Perez, J., Melamed, R., Mathis, D., & Benoist, C. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.010 · Cited by 671 · see citing works
Huehn, J., Siegmund, K., Lehmann, J., Siewert, C., Haubold, U., Feuerer, M., Debes, G. F., Lauber, J., Frey, O., Przybylski, G. K., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20031562 · Cited by 624 · see citing works
Thornton, A. M., Donovan, E. E., Piccirillo, C. A., & Shevach, E. M. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.11.6519 · Cited by 559 · see citing works
Self-citationBettelli, E., Dastrange, M., & Oukka, M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501675102 · Cited by 544 · see citing works
Komatsu, N., Mariotti‐Ferrandiz, E., Wang, Y., MALISSEN, B., Waldmann, H., & Hori, S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811556106 · Cited by 521 · see citing works
IL-17–producing human peripheral regulatory T cells retain suppressive function
Bériou, G., Costantino, C. M., Ashley, C. W., Yang, L., Kuchroo, V. K., Baecher‐Allan, C., & Hafler, D. A. (2009) · Blood · doi:10.1182/blood-2008-10-183251 · Cited by 482 · see citing works
Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells
Ouyang, W., Beckett, O. R., Ma, Q., Paik, J.-H., DePinho, R. A., & Li, M. O. (2010) · Nature Immunology · doi:10.1038/ni.1884 · Cited by 467 · see citing works
The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs
Allan, S. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24685 · Cited by 444 · see citing works
Ko, H. S., Fu, S. M., WINCHESTER, R. J., Yu, D. T. Y., & Kunkel, H. G. (1979) · The Journal of Experimental Medicine · doi:10.1084/jem.150.2.246 · Cited by 439 · see citing works
Hoffmann, P., Eder, R., Boeld, T. J., Doser, K., Piseshka, B., Andreesen, R., & Edinger, M. (2006) · Blood · doi:10.1182/blood-2006-06-027409 · Cited by 405 · see citing works
Eastaff‐Leung, N., Mabarrack, N. H. E., Barbour, A. H., Cummins, A. G., & Barry, S. C. (2009) · Journal of Clinical Immunology · doi:10.1007/s10875-009-9345-1 · Cited by 391 · see citing works
Expansion of Human Regulatory T-Cells From Patients With Type 1 Diabetes
Putnam, A. L., Brusko, T. M., Lee, M. R., Liu, W., Szot, G. L., Ghosh, T., Atkinson, M. A., & Bluestone, J. A. (2008) · Diabetes · doi:10.2337/db08-1168 · Cited by 357 · see citing works
Hoffmann, P., Boeld, T. J., Eder, R., Huehn, J., Floess, S., Wieczorek, G., Olek, S., Dietmaier, W., Andreesen, R., & Edinger, M. (2009) · European Journal of Immunology · doi:10.1002/eji.200838904 · Cited by 356 · see citing works
De novo generation of antigen-specific CD4 + CD25 + regulatory T cells from human CD4 + CD25 – cells
Walker, M., Carson, B. D., Nepom, G. T., Ziegler, S. F., & Buckner, J. H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407691102 · Cited by 283 · see citing works
Duarte, J. H., Zelenay, S., Bergman, M., Martins, A. C., & Demengeot, J. (2009) · European Journal of Immunology · doi:10.1002/eji.200839196 · Cited by 250 · see citing works
Kitoh, A., Ono, M., Naoe, Y., Ohkura, N., Yamaguchi, T., Yaguchi, H., Kitabayashi, I., Tsukada, T., Nomura, T., Miyachi, Y., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.09.003 · Cited by 237 · see citing works
Crellin, N. K., García, R., & Levings, M. K. (2006) · Blood · doi:10.1182/blood-2006-07-035279 · Cited by 234 · see citing works
FOXP3 Promoter Demethylation Reveals the Committed Treg Population in Humans
Janson, P., Winerdal, M. E., Marits, P., Thörn, M., OHLSSON, R. I., & Winqvist, O. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001612 · Cited by 233 · see citing works
Chen, C., Rowell, E. A., Thomas, R. M., Hancock, W. W., & Wells, A. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m608848200 · Cited by 230 · see citing works
Genomic definition of multiple ex vivo regulatory T cell subphenotypes
Feuerer, M., Hill, J. A., Kretschmer, K., von Boehmer, H., Mathis, D. J., & Benoist, C. O. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002006107 · Cited by 213 · see citing works
Passerini, L., Allan, S., Battaglia, M., Nunzio, S. D., McMurchy, A. N., Levings, M. K., Roncarolo, M. G., & Bacchetta, R. (2008) · International Immunology · doi:10.1093/intimm/dxn002 · Cited by 198 · see citing works
Regulatory T cells in transplantation
Karim, M., Bushell, A., & Wood, K. J. (2002) · Current Opinion in Immunology · doi:10.1016/s0952-7915(02)00379-5 · Cited by 188 · see citing works
Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4CD25 T cells
Baecher‐Allan, C., WOLF, E., & Hafler, D. A. (2005) · Clinical Immunology · doi:10.1016/j.clim.2005.02.018 · Cited by 180 · see citing works
TGF-β and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3
Samanta, A., Li, B., Song, X., Bembas, K., Zhang, G., Katsumata, M., Saouaf, S. J., Wang, Q., Hancock, W. W., Shen, Y., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806726105 · Cited by 162 · see citing works
Nagar, M., Jacob‐Hirsch, J., Vernitsky, H., Berkun, Y., Ben‐Horin, S., Amariglio, N., Bank, I., Kloog, Y., Rechavi, G., & Goldstein, I. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902070 · Cited by 150 · see citing works
Induction of oral tolerance to cellular immune responses in the absence of Peyer's patches
Spahn, T. W., Fontana, A., Faria, A. M. C., Slavin, A., Eugster, H., Zhang, X., Koni, P. A., Ruddle, N. H., Flavell, R. A., Rennert, P. D., et al. (2001) · European Journal of Immunology · doi:10.1002/1521-4141(200104)31:4 · Cited by 143 · see citing works
Isolation of CD4+CD25+ Regulatory T Cells for Clinical Trials
Hoffmann, P., Boeld, T. J., Eder, R., Albrecht, J., Doser, K., Piseshka, B., Dada, A. M., Niemand, C., Assenmacher, M., Orsó, E., et al. (2006) · Transplantation and Cellular Therapy · doi:10.1016/j.bbmt.2006.01.005 · Cited by 135 · see citing works
FOXP3 Forkhead Domain Mutation and Regulatory T Cells in the IPEX Syndrome
d'Hennezel, E. B., Ben‐Shoshan, M., Ochs, H. D., Torgerson, T. R., RUSSELL, L. J., Lejtenyi, C., Noya, F., Jabado, N., Mazer, B. D., & Piccirillo, C. A. (2009) · New England Journal of Medicine · doi:10.1056/nejmc0907093 · Cited by 121 · see citing works
Self-citationOberle, N., Eberhardt, N., Falk, C. S., Krammer, P. H., & Suri‐Payer, E. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.6.3578 · Cited by 114 · see citing works
Muriglan, S. J., Ramirez‐Montagut, T., Alpdoğan, Ö., van Huystee, T., Eng, J. M., Hubbard, V. M., Kochman, A. A., Tjoe, K. H., Riccardi, C., Pandolfi, P. P., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20040116 · Cited by 103 · see citing works
FOXP3 ensembles in T‐cell regulation
Li, B., Samanta, A., Song, X., Furuuchi, K., Iacono, K. T., Kennedy, S., Katsumata, M., Saouaf, S. J., & Greene, M. I. (2006) · Immunological Reviews · doi:10.1111/j.0105-2896.2006.00405.x · Cited by 78 · see citing works
Functional Dynamics of Naturally Occurring Regulatory T Cells in Health and Autoimmunity
Levings, M. K., Allan, S., d'Hennezel, E. B., & Piccirillo, C. A. (2006) · Advances in immunology · doi:10.1016/s0065-2776(06)92003-3 · Cited by 53 · see citing works
Self-citationZheng, J. H., Liu, Y., Qin, G., Lam, K., Guan, J. Z., Xiang, Z., Lewis, D. B., Lau, Y., & Tu, W. (2010) · European Journal of Immunology · doi:10.1002/eji.201040724 · Cited by 48 · see citing works
Allogeneic induced human FOXP3+IFN‐γ+ T cells exhibit selective suppressive capacity
Stroopinsky, D., Avivi, I. M., Rowe, J. M., Avigan, D., & Katz, T. (2009) · European Journal of Immunology · doi:10.1002/eji.200839097 · Cited by 28 · see citing works
Natural and Induced Regulatory T Cells
O’Neill, E. J., Sundstedt, A., Mazza, G., Nicolson, K., Ponsford, M., Saurer, L., Streeter, H. B., Anderton, S., & Wraith, D. C. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1309.034 · Cited by 28 · see citing works
Analysis of Human FOXP3+ Treg Cells Phenotype and Function
d'Hennezel, E. B., & Piccirillo, C. A. (2011) · Methods in molecular biology · doi:10.1007/978-1-61737-979-6_13 · Cited by 19 · see citing works
Self-citationInsights into transcriptional regulation by FOXP3
Carson, B. D. (2006) · Frontiers in bioscience · doi:10.2741/1908 · Cited by 14 · see citing works
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Domingo, E., Sheldon, J., & Perales, C. (2012) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.05023-11 · Cited by 1,009 · see citing works
The plasticity and stability of regulatory T cells
Sakaguchi, S., Vignali, D. A. A., Rudensky, A. Y., Niec, R. E., & Waldmann, H. (2013) · Nature reviews. Immunology · doi:10.1038/nri3464 · Cited by 526 · see citing works
Sawant, D. V., & Vignali, D. A. A. (2014) · Immunological Reviews · doi:10.1111/imr.12173 · Cited by 248 · see citing works
CD161 defines the subset of FoxP3+ T cells capable of producing proinflammatory cytokines
Pesenacker, A. M., Bending, D., Ursu, S., Wu, Q., Nistala, K., & Wedderburn, L. R. (2013) · Blood · doi:10.1182/blood-2012-08-443473 · Cited by 175 · see citing works
Lineage stability and phenotypic plasticity of Foxp3+ regulatory T cells
Hori, S. (2014) · Immunological Reviews · doi:10.1111/imr.12175 · Cited by 161 · see citing works
Juvet, S., & Zhang, L. (2012) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjr043 · Cited by 150 · see citing works
Coexpression of TIGIT and FCRL3 Identifies Helios+ Human Memory Regulatory T Cells
Bin Dhuban, K., d’Hennezel, E., Nashi, E., Bar-Or, A., Rieder, S., Shevach, E. M., Nagata, S., & Piccirillo, C. A. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1401803 · Cited by 117 · see citing works
Self-citationEsfahani, K., Al-Aubodah, T.-A., Thebault, P., Lapointe, R., Hudson, M., Johnson, N. A., Baran, D., Bhulaiga, N., Takano, T., Cailhier, J.-F., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-12628-1 · Cited by 109 · see citing works
Self-citationBridle, B. W., Chen, L., Lemay, C. G., Diallo, J., Pol, J. G., Nguyen, A., Capretta, A. A., He, R., Bramson, J. L., Bell, J. C., et al. (2013) · Molecular Therapy · doi:10.1038/mt.2012.265 · Cited by 109 · see citing works
Mechanisms of human FoxP3+ Treg cell development and function in health and disease
Attias, M., Al-Aubodah, T.-A., & Piccirillo, C. A. (2019) · Clinical & Experimental Immunology · doi:10.1111/cei.13290 · Cited by 103 · see citing works
Self-citationJanssen, E., Morbach, H., Ullas, S., Bannock, J. M., Massad, C., Menard, L. C., Barlan, I. B., Lefranc, G., Su, H. C., Dasouki, M., et al. (2014) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2014.07.042 · Cited by 99 · see citing works
T cells out of control—impaired immune regulation in the inflamed joint
Wehrens, E. J., Prakken, B. J., & van Wijk, F. (2012) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2012.149 · Cited by 96 · see citing works
Regulatory T Cells in Central Nervous System Injury: A Double-Edged Sword
Walsh, J. T., Zheng, J., Smirnov, I., Lorenz, U. M., Tung, K. S. K., & Kipnis, J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302401 · Cited by 89 · see citing works
Functional defect in regulatory T cells in myasthenia gravis
Thiruppathi, M., Rowin, J., Jiang, Q. L., Sheng, J. R., Prabhakar, B. S., & Meriggioli, M. N. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06840.x · Cited by 81 · see citing works
Nowak, A., Lock, D., Bächer, P., Hohnstein, T., Vogt, K., Gottfreund, J., Giehr, P., Polansky, J. K., Sawitzki, B., Kaiser, A., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00199 · Cited by 74 · see citing works
Cheng, Y., Wong, M. T., van der Maaten, L., & Newell, E. W. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501928 · Cited by 67 · see citing works
Molecular Determinants of Regulatory T Cell Development: The Essential Roles of Epigenetic Changes
Kitagawa, Y., Ohkura, N., & Sakaguchi, S. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00106 · Cited by 61 · see citing works
IPEX syndrome from diagnosis to cure, learning along the way
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Suppression by human FOXP3 + regulatory T cells requires FOXP3-TIP60 interactions
Dhuban, K. B., d'Hennezel, E. B., Nagai, Y., Xiao, Y., Shao, S., Istomine, R., Alvarez, F., Ben‐Shoshan, M., Ochs, H. D., Mazer, B. D., et al. (2017) · Science Immunology · doi:10.1126/sciimmunol.aai9297 · Cited by 57 · see citing works
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Dhuban, K. B., Kornete, M., Mason, E. S., & Piccirillo, C. A. (2014) · Immunological Reviews · doi:10.1111/imr.12168 · Cited by 53 · see citing works
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Walsh, J. T., Watson, N., & Kipnis, J. (2014) · Immunology · doi:10.1111/imm.12187 · Cited by 52 · see citing works
Functional stability of Foxp3+ regulatory T cells
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Self-citationKaufman, G., Massoud, A. H., Dembele, M., Yona, M., Piccirillo, C. A., & Mazer, B. D. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00469 · Cited by 50 · see citing works
Self-citationRegulatory T Cell Responses to High-Dose Methylprednisolone in Active Systemic Lupus Erythematosus
Mathian, A., Jouenne, R., Chader, D., Aubart, F. C., Haroche, J., Fadlallah, J., Claër, L., Musset, L., Gorochov, G., Amoura, Z., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143689 · Cited by 50 · see citing works
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Hasib, L., Lundberg, A. K., Zachrisson, H., Ernerudh, J., & Jonasson, L. (2015) · Journal of Internal Medicine · doi:10.1111/joim.12398 · Cited by 44 · see citing works
Forkhead box P3: The Peacekeeper of the Immune System
Passerini, L., de Sio, F. R. S., Roncarolo, M. G., & Bacchetta, R. (2013) · International Reviews of Immunology · doi:10.3109/08830185.2013.863303 · Cited by 40 · see citing works
Mechanisms of TREG cell adaptation to inflammation
Alvarez, F., Al-Aubodah, T.-A., Yang, Y. H., & Piccirillo, C. A. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.1mr0120-196r · Cited by 40 · see citing works
Self-citationRegulatory Cells and Transplantation TolerancePreprint
Cobbold, S. P., & Waldmann, H. (2013) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a015545 · Cited by 39 · see citing works
The importance of being a regulatory T cell in pregnancy
Clark, D. A. (2016) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2016.04.288 · Cited by 39 · see citing works
Nettenstrom, L. M., Alderson, K. L., Raschke, E. E., Evans, M. D., Sondel, P. M., Olek, S., & Seroogy, C. M. (2012) · Journal of Immunological Methods · doi:10.1016/j.jim.2012.09.014 · Cited by 38 · see citing works
Spectrum of T‐lymphocyte activities regulating allergic lung inflammation
Gelfand, E. W., Joetham, A., Wang, M., Takeda, K., & Schedel, M. (2017) · Immunological Reviews · doi:10.1111/imr.12561 · Cited by 32 · see citing works
A novel subpopulation of monocyte-like cells in the human lung after lipopolysaccharide inhalation
Brittan, M., Barr, L. C., Morris, A. C., Duffin, R., Rossi, F., Johnston, S., Monro, G., Anderson, N., Rossi, A. G., McAuley, D. F., et al. (2012) · European Respiratory Journal · doi:10.1183/09031936.00113811 · Cited by 31 · see citing works
Epigenetic Modification of the FoxP3 TSDR in HAM/TSP Decreases the Functional Suppression of Tregs
Anderson, M. R., Enose‐Akahata, Y., Massoud, R., Ngouth, N., Tanaka, Y., Oh, U., & Jacobson, S. (2014) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-014-9547-z · Cited by 30 · see citing works
Baatjes, A. J., Smith, S. G., WATSON, R. M., Howie, K. J., Murphy, D. M., Larché, M., Denburg, J. A., Inman, M. D., & O’Byrne, P. M. (2015) · Clinical & Experimental Allergy · doi:10.1111/cea.12594 · Cited by 29 · see citing works
Miyara, M., Chader, D., Burlion, A., Goldstein, J. D., Sterlin, D., Norol, F., Trebeden‐Negre, H., Claër, L., Sakaguchi, S., Marodon, G., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.10914 · Cited by 29 · see citing works
Epigenetic dynamics during CD4+ T cells lineage commitment
Rodríguez, R. M. A., López‐Larrea, C., & Suárez-Álvarez, B. (2015) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2015.04.020 · Cited by 28 · see citing works
Signaling Through gp130 Compromises Suppressive Function in Human FOXP3+ Regulatory T Cells
Dhuban, K. B., Bartolucci, S., d'Hennezel, E. B., & Piccirillo, C. A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01532 · Cited by 27 · see citing works
Self-citationQuispel, W. T., Stegehuis-Kamp, J. A., Santos, S. J., Egeler, R. M., & van Halteren, A. G. S. (2015) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2014.0190 · Cited by 27 · see citing works
Regulatory T Cells and Transplantation Tolerance
Hilbrands, R., Howie, D., Cobbold, S. P., & Waldmann, H. (2013) · Immunotherapy · doi:10.2217/imt.13.69 · Cited by 25 · see citing works
Developmental Plasticity of Murine and Human Foxp3+ Regulatory T Cells
Liston, A., & Piccirillo, C. A. (2013) · Advances in immunology · doi:10.1016/b978-0-12-407707-2.00003-5 · Cited by 23 · see citing works
Self-citationT regulatory cell therapy in transplantation
MacDonald, K. G., Orban, P. C., & Levings, M. K. (2012) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e328355aaaf · Cited by 22 · see citing works
Hetemäki, I., Jarva, H., Kluger, N., Baldauf, H., Laakso, S. M., Bratland, E., Husebye, E. S., Kisand, K. E., Ranki, A., Peterson, P., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1500301 · Cited by 18 · see citing works
Different phenotypes of CD4+CD25+Foxp3+ regulatory T cells in recipients post liver transplantation
Wang, K., Song, Z., Wu, B., Zhou, C., Liu, W., & Gao, W. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.01.048 · Cited by 17 · see citing works
Massoud, A. H., Kaufman, G., Xue, D., Béland, M., Dembele, M., Piccirillo, C. A., Mourad, W. M., & Mazer, B. D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1502361 · Cited by 17 · see citing works
Self-citationHuman regulatory T cells suppress proliferation of B lymphoma cells
Grygorowicz, M. A., Biernacka, M., Bujko, M., Nowak, E., Rymkiewicz, G., Paszkiewicz‐Kozik, E., Borycka, I. S., Bystydzieński, Z., Walewski, J. A., & Markowicz, S. (2016) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.3109/10428194.2015.1121260 · Cited by 16 · see citing works
He, H., Ni, B., Tian, Y., Tian, Z., Chen, Y., Liu, Z., Yang, X., Lv, Y., & Zhang, Y. (2013) · Immunology · doi:10.1111/imm.12198 · Cited by 16 · see citing works
The Molecular Control of Regulatory T Cell Induction
van Nieuwenhuijze, A. E. M., & Liston, A. (2015) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2015.09.001 · Cited by 16 · see citing works
Functional plasticity in human FOXP3 + regulatory T cells
d'Hennezel, E. B., & Piccirillo, C. A. (2012) · Human Vaccines & Immunotherapeutics · doi:10.4161/hv.20203 · Cited by 14 · see citing works
Self-citationShukri, N. D. M., Izati, A. F., Ghazali, W. S. W., Hussin, C. M. C., & Wong, K. K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.675250 · Cited by 14 · see citing works
Hill, D. L., Eastaff‐Leung, N., Bresatz, S., Warner, N. L., Ruitenberg, J. J., Krumbiegel, D., Pederson, S., McInnes, N. J., Brown, C. Y., Sadlon, T. J., et al. (2012) · Immunology and Cell Biology · doi:10.1038/icb.2012.18 · Cited by 14 · see citing works
Therapeutic application of T regulatory cells in composite tissue allotransplantation
Yang, J.-H., & Eun, S. (2017) · Journal of Translational Medicine · doi:10.1186/s12967-017-1322-5 · Cited by 14 · see citing works
Liao, J., Li, Y., Li, X., Su, X., Peng, J., Xiao, N., Fan, X., Chen, H., Lu, G., Lin, G., et al. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108960 · Cited by 13 · see citing works
Zhang, Y., Li, L., Genest, G., Zhao, W., Ke, D., Bartolucci, S., Pavey, N., Al-Aubodah, T.-A., Lejtenyi, D., Torabi, B., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.705615 · Cited by 13 · see citing works
Self-citationCD90+ Human Dermal Stromal Cells Are Potent Inducers of FoxP3+ Regulatory T Cells
Pfisterer, K., Lipnik, K., Hofer, E., & Elbe‐Bürger, A. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.309 · Cited by 13 · see citing works
Elhage, R., Cheraï, M., Levacher, B., Darrasse-Jèze, G., Baillou, C., Zhao, X., Khatib, A., Piaggio, E., & Klatzmann, D. (2015) · Scandinavian Journal of Immunology · doi:10.1111/sji.12275 · Cited by 13 · see citing works
Stabilizing Human Regulatory T Cells for Tolerance Inducing Immunotherapy
He, X., Koenen, H. J. P. M., Slaats, J., & Joosten, I. (2017) · Immunotherapy · doi:10.2217/imt-2017-0017 · Cited by 11 · see citing works
Dysregulated T-cell homeostasis and decreased CD30+ Treg proliferating in aplastic anemia
Sun, N., Zhang, M., Kong, J., Li, J., Dong, Y., Wang, X., Fu, L., Zhou, Y., Chen, Y., Li, Y., et al. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e35775 · Cited by 8 · see citing works
Dysfunctional regulatory T cell: May be an obstacle to immunotherapy in cardiovascular diseases
Zhang, Y.-S., & Chen, Y. (2024) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2024.116359 · Cited by 8 · see citing works
Kaneko, S. (2013) · Journal of Molecular Biomarkers & Diagnosis · doi:10.4172/2155-9929.s5-005 · Cited by 7 · see citing works
Koivula, T., Tuulasvaara, A., Hetemäki, I., Hurme, M., Mäkelä, S., Mustonen, J., Vaheri, A., & Arstila, T. (2017) · Pathogens and Disease · doi:10.1093/femspd/ftw114 · Cited by 6 · see citing works
", Сергеевич, Б. А., Khantakova, J. N., Fisher, M. S., Tereshchenko, V., Васильевич, К. В., Сергеевна, Ш. Н., & Sennikov, S. V. (2023) · Immunologiya · doi:10.33029/0206-4952-2023-44-2-147-156 · Cited by 4 · see citing works
Ait‐Oufella, H., & Tedgui, A. (2016) · Circulation Research · doi:10.1161/circresaha.116.308805 · Cited by 4 · see citing works
Physiology and Pathology of Immune Dysregulation: Regulatory T Cells and Anergy
Tores, M. I., López‐Casado, M. Á., de León, C. P., Lorite, P., & Palomeque, T. (2017) · InTech eBooks · doi:10.5772/intechopen.71770 · Cited by 3 · see citing works
FOCIS Goes South: Advances in Translational and Clinical Immunology
Kalergis, A. M., Anegón, I., & González, P. A. (2017) · Immunotherapy · doi:10.2217/imt-2017-0079 · Cited by 1 · see citing works
Single-Cell Omics in Human Reproductive Medicine—Our Clinical Experiences in Single-Cell Therapy
Kaneko, S., & Takamatsu, K. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-817532-3.00012-8 · Cited by 1 · see citing works
He, H., & Lv, Y. (2012) · Haematologica · doi:10.3324/haematol.2011.061689 · Cited by 1 · see citing works
Vive la résistance! How T cells escape regulation in autoimmune inflammation
Wehrens, E. J. (2013) · Utrecht University Repository (Utrecht University)
Fanelli, G. (2013) · IRIS Research product catalog (Sapienza University of Rome)
Newell, E. W., Cheng, Y., Wong, M. T., & van der Maaten, L. J. P. (2015)
Comment on "Stability of human rapamycin- expanded CD4
He, H., & Lv, Y. (2012)
Wells, J. C. (2015) · UWE Research Repository (UWE Bristol)
马, 新. (2025) · Journal of Clinical Personalized Medicine · doi:10.12677/jcpm.2025.46498
- Authors
- d’Hennezel, E., Yurchenko, E., Sgouroudis, E., Hay, V., & Piccirillo, C. A.
- Affiliations
- Department of Microbiology and Immunology, McGill University , Montreal, Quebec H3A 2B4 ,
- McGill University Health Centre (CA)
- Corresponding author
- Piccirillo, Ciriaco A
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-06
- Volume
- 186
- Issue
- 12
- Pages
- 6788-6797
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2098155999
- Cited by
- 73
- References
- 61
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 5 · 2018: 1 · 2017: 8 · 2016: 6 · 2015: 12 · 2014: 8 · 2013: 12 · 2012: 12
- FWCI
- 4.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- McGill University
- McGill University Health Centre
- Canadian Institutes of Health Research (MOP84041)
- 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 › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Keywords
- regulatory T cells, Foxp3, functional heterogeneity, suppressive function, CD4+CD25high T cells, CD45RO+ memory T cells, T cell reactivation, T cell plasticity, self-tolerance, single-cell cloning
- MeSH terms
- Clone Cells, Humans, Immunologic Memory, Lymphocyte Activation, Biomarkers, Antigens, CD, Self Tolerance, Inflammation Mediators, T-Lymphocytes, Regulatory, Forkhead Transcription Factors
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