Genetic Reprogramming of Primary Human T Cells Reveals Functional Plasticity in Th Cell Differentiation
Abstract
Activation of naive T cells through the TCR and cytokine signals directs their differentiation into effector or memory subsets with different cytokine profiles. Here, we tested the flexibility of human Th1 or Th2 differentiation by forced expression of transcription factors T-bet and GATA-3. Ectopic expression of T-bet and GATA-3 in freshly isolated human TN cells resulted in their differentiation to a Th1 and Th2 phenotype, respectively, in the absence of polarizing cytokines. Introduction of GATA-3 into lineage-committed Th1 cells induced the expression of Th2-specific cytokines (IL-4 and IL-5) and chemotactic receptors (CCR4, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). However, these cells partially maintained their Th1-specific profile (IFN-γ and IL-12Rβ2 expression). Conversely, expression of T-bet in lineage-committed Th2 cells caused a more profound switch to the Th1 phenotype, including the up-regulation of CXCR3 and down-regulation of CCR4 and CRTH2. Interestingly, similar to the naive T cell subset, central memory T cells were also largely programmed toward Th1 or Th2 effector cells upon expression of T-bet and GATA-3, respectively. However, expression of these transcription factors in effector memory T cells was much less influential on cytokine and chemokine receptor expression profiles. Our results reveal remarkable plasticity in the differentiation programs of human memory T cells. This flexibility is progressively diminished as cells mature from naive to effector T cells. These findings have important implications in understanding the molecular mechanisms of human T cell differentiation and for devising novel therapeutic strategies aimed at immunomodulation of skewed effector T cell responses.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The specific interaction of CCR4 on Th2 cells with CCL17 and CCL22 is critical for movement of Tmem into the skin.
“The specific interaction of CCR4 on Th2 cells with CCL17 and CCL22 is critical for the movement of Tmem into the skin [186].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [186]
Cites
Two subsets of memory T lymphocytes with distinct homing potentials and effector functions
Sallusto, F., Lenig, D., Förster, R., Lipp, M., & Lanzavecchia, A. (1999) · Nature · doi:10.1038/44385 · Cited by 5,846 · see citing works
Functional diversity of helper T lymphocytes
Abbas, A. K., MURPHY, K. M. M., & Sher, A. (1996) · Nature · doi:10.1038/383787a0 · Cited by 4,383 · see citing works
The expanding universe of T-cell subsets: Th1, Th2 and more
Mosmann, T. R., & Sad, S. (1996) · Immunology Today · doi:10.1016/0167-5699(96)80606-2 · Cited by 3,603 · 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
Zheng, W.-P., & Flavell, R. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80240-8 · Cited by 2,384 · see citing works
Kuchroo, V. K., Das, M. P., Brown, J. A., Ranger, A. M., Zamvil, S. S., Sobel, R. A., Weiner, H. L., Nabavi, N., & Glimcher, L. H. (1995) · Cell · doi:10.1016/0092-8674(95)90349-6 · Cited by 1,642 · see citing works
Acquisition of lymphokine-producing phenotype by CD4+ T cells
Seder, R. A., & Paul, W. E. (1994) · Annual Review of Immunology · doi:10.1146/annurev.iy.12.040194.003223 · Cited by 1,557 · see citing works
Cytokines Induce the Development of Functionally Heterogeneous T Helper Cell Subsets
O’Garra, A. (1998) · Immunity · doi:10.1016/s1074-7613(00)80533-6 · Cited by 1,535 · see citing works
Szabo, S. J., Sullivan, B. M., Stemmann, C., Satoskar, A. R., Sleckman, B. P., & Glimcher, L. H. (2002) · Science · doi:10.1126/science.1065543 · Cited by 1,172 · see citing works
Hirai, H., Tanaka, K., Yoshie, O., Ogawa, K., Kenmotsu, K., Takamori, Y., Ichimasa, M., Sugamura, K., Nakamura, M., Takano, S., et al. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.2.255 · Cited by 1,101 · see citing works
Self-citationT-bet is a STAT1-induced regulator of IL-12R expression in naïve CD4+ T cells
Afkarian, M., Šedý, J. R., Yang, J., Jacobson, N. G., Cereb, N., Yang, S. Y., Murphy, T. L., & MURPHY, K. M. M. (2002) · Nature Immunology · doi:10.1038/ni794 · Cited by 1,038 · see citing works
The Role of Chemokine Receptors in Primary, Effector, and Memory Immune Responses
Sallusto, F., Mackay, C. R., & Lanzavecchia, A. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.593 · Cited by 1,037 · see citing works
Szabo, S. J., Dighe, A. S., Gubler, U., & MURPHY, K. M. M. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.5.817 · Cited by 973 · see citing works
Helper T Cell Differentiation Is Controlled by the Cell Cycle
Bird, J. J., Brown, D. R., Mullen, A. C., Moskowitz, N. H., Mahowald, M. A., Sider, J. R., Gajewski, T. F., Wang, C.-R., & Reiner, S. L. (1998) · Immunity · doi:10.1016/s1074-7613(00)80605-6 · Cited by 834 · see citing works
Role of T-bet in Commitment of T H 1 Cells Before IL-12-Dependent Selection
Mullen, A. C., High, F. A., Hutchins, A. S., Lee, H. W., Villarino, A. V., Livingston, D. M., Kung, A. L., Cereb, N., Yao, T., Yang, S. Y., et al. (2001) · Science · doi:10.1126/science.1059835 · Cited by 825 · see citing works
Mig and IP-10: CXC chemokines that target lymphocytes
Farber, J. M. (1997) · Journal of Leukocyte Biology · doi:10.1002/jlb.61.3.246 · Cited by 788 · see citing works
T-bet is rapidly induced by interferon-γ in lymphoid and myeloid cells
Lighvani, A. A., Frucht, D. M., Jankovic, D., Yamane, H., Aliberti, J., Hissong, B. D., Nguyen, B. V., Gadina, M., Sher, A., Paul, W. E., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.261570598 · Cited by 783 · see citing works
Inhibition of Th1 Development Mediated by GATA-3 through an IL-4-Independent Mechanism
Ouyang, W., Ranganath, S. H., Weindel, K., Bhattacharya, D., Murphy, T. L., Sha, W. C., & MURPHY, K. M. M. (1998) · Immunity · doi:10.1016/s1074-7613(00)80671-8 · Cited by 778 · see citing works
Selective Expression of an Interleukin-12 Receptor Component by Human T Helper 1 Cells
Rogge, L., Barberis-Maino, L., Biffi, M., Passini, N., Presky, D. H., Gubler, U., & Sinigaglia, F. (1997) · The Journal of Experimental Medicine · doi:10.1084/jem.185.5.825 · Cited by 766 · see citing works
Stat6-Independent GATA-3 Autoactivation Directs IL-4-Independent Th2 Development and Commitment
Ouyang, W., Löhning, M., Gao, Z., Assenmacher, M., Ranganath, S. H., Radbruch, A., & MURPHY, K. M. M. (2000) · Immunity · doi:10.1016/s1074-7613(00)80156-9 · Cited by 702 · see citing works
Modulation of Chromatin Structure Regulates Cytokine Gene Expression during T Cell Differentiation
Agarwal, S., & Rao, A. (1998) · Immunity · doi:10.1016/s1074-7613(00)80642-1 · Cited by 687 · see citing works
Constant, S. L., Pfeiffer, C., Woodard, A., Pasqualini, T., & Bottomly, K. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.182.5.1591 · Cited by 677 · see citing works
The Proto-Oncogene c-maf Is Responsible for Tissue-Specific Expression of Interleukin-4
Ho, I., Hodge, M. R., Rooney, J. W., & Glimcher, L. H. (1996) · Cell · doi:10.1016/s0092-8674(00)81299-4 · Cited by 667 · see citing works
Zhang, D.-H., Cohn, L. E., Ray, P., Bottomly, K., & Ray, A. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.34.21597 · Cited by 665 · see citing works
Human Immunodeficiency Virus Type 1 Spinoculation Enhances Infection through Virus Binding
O’Doherty, U., Swiggard, W. J., & Malim, M. H. (2000) · Journal of Virology · doi:10.1128/jvi.74.21.10074-10080.2000 · Cited by 665 · see citing works
Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet
Finotto, S., Neurath, M. F., Glickman, J. N., Qin, S., Lehr, H. A., Green, F. H. Y., Ackerman, K. G., Haley, K. J., Galle, P. R., Szabo, S. J., et al. (2002) · Science · doi:10.1126/science.1065544 · Cited by 627 · see citing works
Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection
Hancock, W. W., Lu, B., Gao, W., Csizmadia, V., Faia, K., King, J. A., Smiley, S. T., Ling, M., Gerard, N. P., & Gerard, C. J. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.10.1515 · Cited by 617 · see citing works
Neurath, M. F., Weigmann, B., Finotto, S., Glickman, J. N., Nieuwenhuis, E. E. S., Iijima, H., Mizoguchi, A., Mizoguchi, E., Mudter, J., Galle, P. R., et al. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20011956 · Cited by 606 · see citing works
Geginat, J., Sallusto, F., & Lanzavecchia, A. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.12.1711 · Cited by 533 · see citing works
TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes
Avni, O., Lee, D. H., Macián, F., Szabo, S. J., Glimcher, L. H., & Rao, A. (2002) · Nature Immunology · doi:10.1038/ni808 · Cited by 521 · see citing works
Early Transcription and Silencing of Cytokine Genes Underlie Polarization of T Helper Cell Subsets
Grogan, J. L., Mohrs, M., Harmon, B., Lacy, D. A., Sedat, J. W., & Locksley, R. M. (2001) · Immunity · doi:10.1016/s1074-7613(01)00103-0 · Cited by 485 · see citing works
Transcriptional regulation of Th1/Th2 polarization
Rengarajan, J., Szabo, S. J., & Glimcher, L. H. (2000) · Immunology Today · doi:10.1016/s0167-5699(00)01712-6 · Cited by 433 · see citing works
Cytokine Signals Are Sufficient for HIV-1 Infection of Resting Human T Lymphocytes
Unutmaz, D., KewalRamani, V. N., Marmon, S., & Littman, D. R. (1999) · The Journal of Experimental Medicine · doi:10.1084/jem.189.11.1735 · Cited by 427 · see citing works
Self-citationLee, H. J., Takemoto, N., Kurata, H., Kamogawa, Y., Miyatake, S., O'Garra, A., & Arai, N. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.192.1.105 · Cited by 393 · see citing works
The Transcription Factor c-Maf Controls the Production of Interleukin-4 but Not Other Th2 Cytokines
Kim, J. I., Ho, I., Grusby, M. J., & Glimcher, L. H. (1999) · Immunity · doi:10.1016/s1074-7613(00)80073-4 · Cited by 383 · see citing works
From TCR Engagement to T Cell Activation
Lanzavecchia, A., Iezzi, G., & Viola, A. (1999) · Cell · doi:10.1016/s0092-8674(00)80952-6 · Cited by 380 · see citing works
Selective Expression of a Novel Surface Molecule by Human Th2 Cells In Vivo
Nagata, K., Tanaka, K., Ogawa, K., Kemmotsu, K., Imai, T., Yoshie, O., Abé, H., Tada, K., Nakamura, M., Sugamura, K., et al. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.3.1278 · Cited by 377 · see citing works
Self-citationSauty, A., Dziejman, M., Taha, R. A., Iarossi, A. S., Neote, K. S., García-Zepeda, E. A., Hamid, Q. A., & Luster, A. D. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.6.3549 · Cited by 373 · see citing works
Zhang, D.-H., Yang, L.-Y., Cohn, L., Parkyn, L., Homer, R. J., Ray, P., & Ray, A. (1999) · Immunity · doi:10.1016/s1074-7613(00)80122-3 · Cited by 364 · see citing works
Ho, I., Vorhees, P., Marín, N., Oakley, B. K., Tsai, S., Orkin, S. H., & Leiden, J. M. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb08059.x · Cited by 349 · see citing works
Messi, M., Giacchetto, I., Nagata, K., Lanzavecchia, A., Natoli, G., & Sallusto, F. (2002) · Nature Immunology · doi:10.1038/ni872 · Cited by 347 · see citing works
Self-citationHlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction
Mullen, A. C., Hutchins, A. S., High, F. A., Lee, H. W., Sykes, K. J., Chodosh, L. A., & Reiner, S. L. (2002) · Nature Immunology · doi:10.1038/ni807 · Cited by 306 · see citing works
Ho, I., Lo, D. D., & Glimcher, L. H. (1998) · The Journal of Experimental Medicine · doi:10.1084/jem.188.10.1859 · Cited by 303 · see citing works
β cells are responsible for CXCR3-mediated T-cell infiltration in insulitis
Frigerio, S., Junt, T., Lu, B., Gerard, C. J., Zumsteg, U., Holländer, G. A., & Piali, L. (2002) · Nature Medicine · doi:10.1038/nm1202-792 · Cited by 302 · see citing works
Kurata, H., Lee, H. J., O’Garra, A., & Arai, N. (1999) · Immunity · doi:10.1016/s1074-7613(00)80142-9 · Cited by 299 · see citing works
Nagata, K., Hirai, H., Tanaka, K., Ogawa, K., Asô, T., Sugamura, K., Nakamura, M., & Takano, S. (1999) · FEBS Letters · doi:10.1016/s0014-5793(99)01251-x · Cited by 297 · see citing works
Self-citationCook, E. B., Stahl, J. L., Lowe, L., Chen, R., Morgan, E., Wilson, J., Varro, R., Chan, A., Graziano, F. M., & Barney, N. P. (2001) · Journal of Immunological Methods · doi:10.1016/s0022-1759(01)00407-0 · Cited by 285 · see citing works
Andrew, D. P., Chang, M., McNinch, J. S., Wathen, S. T., Rihanek, M., Tseng, J., Spellberg, J. P., & Elias, C. G. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.9.5027 · Cited by 266 · see citing works
Tao, X., Constant, S. L., Jorritsma, P. J., & Bottomly, K. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.159.12.5956 · Cited by 265 · see citing works
Kawasaki, S., Takizawa, H., Yoneyama, H., Nakayama, T., Fujisawa, R., Izumizaki, M., Imai, T., Yoshie, O., Homma, I., Yamamoto, K., et al. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.3.2055 · Cited by 261 · see citing works
Regulation of IL-4 Gene Expression by Distal Regulatory Elements and GATA-3 at the Chromatin Level
Lee, G. R., Fields, P. E., & Flavell, R. A. (2001) · Immunity · doi:10.1016/s1074-7613(01)00125-x · Cited by 240 · see citing works
Ho, I., & Glimcher, L. H. (2002) · Cell · doi:10.1016/s0092-8674(02)00705-5 · Cited by 233 · see citing works
Cutting Edge: Differential Responsiveness of the IL-5 and IL-4 Genes to Transcription Factor GATA-3
Zhang, D.-H., Yang, L., & Ray, A. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.8.3817 · Cited by 229 · see citing works
Differential responsiveness of the IL-5 and IL-4 genes to transcription factor GATA-3.
Zhang, D.-H., Yang, L., & Ray, A. (1998) · PubMed · Cited by 226 · see citing works
GATA-3-dependent enhancer activity in IL-4 gene regulation.
Ranganath, S. H., Ouyang, W., Bhattarcharya, D., Sha, W. C., Grupe, A., Peltz, G., & MURPHY, K. M. M. (1998) · PubMed · Cited by 201 · see citing works
Selective Export of MHC Class I Molecules from the ER after Their Dissociation from TAP
Spiliotis, E. T., Osorio, M., Zúñiga, M. C., et al. (2000) · Immunity · doi:10.1016/s1074-7613(00)00081-9 · Cited by 201 · see citing works
Ferber, I., Lee, H., Zonin, F., Heath, V. L., Mui, A., Arai, N., & O’Garra, A. (1999) · Clinical Immunology · doi:10.1006/clim.1999.4718 · Cited by 172 · see citing works
Cutting Edge: GATA-3-Dependent Enhancer Activity in IL-4 Gene Regulation
Ranganath, S. H., Ouyang, W., Bhattarcharya, D., Sha, W. C., Grupe, A., Peltz, G., & MURPHY, K. M. M. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.8.3822 · Cited by 166 · see citing works
Mast cells in autoimmune disease
Benoist, C., & Mathis, D. (2002) · Nature · doi:10.1038/nature01324 · Cited by 163 · see citing works
The Cell Type-Specific Expression of the Murine IL-13 Gene Is Regulated by GATA-3
Kishikawa, H., Sun, J., Choi, A., Miaw, S., & Ho, I. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.8.4414 · Cited by 153 · 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
ROG, Repressor of GATA, Regulates the Expression of Cytokine Genes
Miaw, S., Choi, A., Yu, E., Kishikawa, H., & Ho, I. (2000) · Immunity · doi:10.1016/s1074-7613(00)80185-5 · Cited by 138 · see citing works
Geginat, J., Sallusto, F., & Lanzavecchia, A. (2003) · Pathologie Biologie · doi:10.1016/s0369-8114(03)00098-1 · Cited by 120 · see citing works
Friend of GATA-1 Represses GATA-3–dependent Activity in CD4+ T Cells
Zhou, M., Ouyang, W., Gong, Q., Katz, S. G., White, J. M., Orkin, S. H., & MURPHY, K. M. M. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.10.1461 · Cited by 87 · see citing works
Functional plasticity of an antigen-specific memory CD4 T cell population
Ahmadzadeh, M., & Färber, D. L. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192263099 · Cited by 69 · see citing works
Lack of IL-12 signaling in human allergen-specific Th2 cells
Hilkens, C. M. U., Messer, G., Tesselaar, K., et al. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.10.4316 · Cited by 60 · see citing works
Kurata, H., Lee, H., McClanahan, T., Coffman, R. L., O’Garra, A., & Arai, N. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.9.4538 · Cited by 53 · see citing works
Heath, V. L., Showe, L. C., Crain, C., Barrat, F. J., Trinchieri, G., & O’Garra, A. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.6.2861 · Cited by 48 · see citing works
Rodriguez-Palmero, M. (1999) · doi:10.1002/(sici)1521-4141(199912)29:12
Flagged first, then by citations
Cited by
Sorted by citations
Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance
Sallusto, F., Geginat, J., & Lanzavecchia, A. (2004) · Annual Review of Immunology · doi:10.1146/annurev.immunol.22.012703.104702 · Cited by 3,067 · see citing works
Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
Cossarizza, A., Chang, H., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andrä, I., Andreata, F., Annunziato, F., Arranz, E., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202170126 · Cited by 531 · see citing works
Kanhere, A., Hertweck, A., Bhatia, U., Gökmen, M. R., Perucha, E., Jackson, I., Lord, G. M., & Jenner, R. G. (2012) · Nature Communications · doi:10.1038/ncomms2260 · Cited by 345 · see citing works
T-bet is required for optimal proinflammatory CD4+ T-cell trafficking
Lord, G. M. (2005) · Blood · doi:10.1182/blood-2005-04-1393 · Cited by 270 · see citing works
T-helper cell type-2 regulation in allergic disease
Georas, S. N., Guo, J., De Fanis, U., & Casolaro, V. (2005) · European Respiratory Journal · doi:10.1183/09031936.05.00006005 · Cited by 181 · see citing works
- Authors
- Sundrud, M. S., Grill, S. M., Ni, D., Nagata, K., Alkan, S. S., Subramaniam, A., & Unutmaz, D.
- Affiliations
- Vanderbilt University (US)
- Aventis Pharmaceuticals, Immunology Platform , Bridgewater, NJ 08807
- BML (Japan) (JP)
- Corresponding author
- Unutmaz, Derya
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2003-10-01
- Volume
- 171
- Issue
- 7
- Pages
- 3542-3549
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2167132998
- Cited by
- 112
- References
- 69
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2021: 3 · 2020: 1 · 2019: 3 · 2018: 5 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 3 · 2013: 6 · 2012: 2
- FWCI
- 3.46
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- 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 › Developmental Biology and Gene Regulation
- Keywords
- T cell differentiation, T-bet, GATA3, transcription factors, naive T cells, central memory T cells, effector memory T cells, chemokine receptor expression, CCR4, CXCR3, CRTH2, IL-4, IL-5, interferon-gamma, IL-12Rβ2, T cell activation
- MeSH terms
- T-bet Transcription Factor, Adult, Cell Differentiation, DNA-Binding Proteins, Genetic Vectors, T-Lymphocytes, Helper-Inducer, Humans, Immunologic Memory, Interphase, Lymphocyte Activation, Transcription Factors, Trans-Activators, T-Lymphocyte Subsets, Th1 Cells, Th2 Cells, Cell Lineage, T-Box Domain Proteins, GATA3 Transcription Factor
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
