Essential autocrine regulation by IL-21 in the generation of inflammatory T cells
Abstract
After activation, CD4+ helper T (T(H)) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function. During this differentiation, T(H)1 and T(H)2 cells produce interferon-gamma and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct T(H) subset, termed T(HIL-17), T(H)17 or inflammatory T(H) (T(H)i), has been recently identified as a distinct T(H) lineage mediating tissue inflammation. T(H)17 differentiation is initiated by transforming growth factor-beta and IL-6 (refs 5-7) and reinforced by IL-23 (ref. 8), in which signal transduction and activators of transcription (STAT)3 and retinoic acid receptor-related orphan receptor (ROR)-gamma mediate the lineage specification. T(H)17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in T(H)17 differentiation. Here we show that IL-21 is another cytokine highly expressed by mouse T(H)17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-gamma. IL-21 potently induces T(H)17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-gamma, which is encoded by Rorc. IL-21 deficiency impairs the generation of T(H)17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and n…
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?
STAT3 is essential for Th17 differentiation mediated by IL-6/TGF-β/IL-21 and by IL-23/STAT3.
“STAT3 is also essential for Th17 differentiation mediated by IL-6/transforming growth factor (TGF)-β/IL-21”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Nurieva et al., 2007
Cites
Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., & Kuchroo, V. K. (2006) · Nature · doi:10.1038/nature04753 · Cited by 6,992 · see citing works
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., & Littman, D. R. (2006) · Cell · doi:10.1016/j.cell.2006.07.035 · Cited by 5,145 · see citing works
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M., & Stockinger, B. (2006) · Immunity · doi:10.1016/j.immuni.2006.01.001 · Cited by 3,605 · see citing works
Th17: An Effector CD4 T Cell Lineage with Regulatory T Cell Ties
Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M., & Murphy, K. M. (2006) · Immunity · doi:10.1016/j.immuni.2006.06.002 · Cited by 1,422 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009) · Annual Review of Immunology · doi:10.1146/annurev.immunol.021908.132710 · Cited by 4,873 · see citing works
Differentiation of Effector CD4 T Cell Populations
Zhu, J., Yamane, H., & Paul, W. E. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101212 · Cited by 3,452 · see citing works
Follicular Helper CD4 T Cells (T <sub>FH</sub> )
Crotty, S. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-031210-101400 · Cited by 2,738 · see citing works
Kaser, A., Zeissig, S., & Blumberg, R. S. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101225 · Cited by 1,806 · see citing works
Ivanov, I. I., Frutos, R. D. L., Manel, N., Yoshinaga, K., Rifkin, D. B., Sartor, R. B., Finlay, B. B., & Littman, D. R. (2008) · Cell Host & Microbe · doi:10.1016/j.chom.2008.09.009 · Cited by 1,770 · see citing works
T Helper 17 Lineage Differentiation Is Programmed by Orphan Nuclear Receptors RORα and RORγ
Yang, X. O., Pappu, B. P., Nurieva, R., Akimzhanov, A., Kang, H. S., Chung, Y., Ma, L., Shah, B., Panopoulos, A. D., Schluns, K. S., et al. (2008) · Immunity · doi:10.1016/j.immuni.2007.11.016 · Cited by 1,605 · see citing works
Self-citationThe IL-23-IL-17 immune axis: from mechanisms to therapeutic testing
Gaffen, S. L., Jain, R., Garg, A. V., & Cua, D. J. (2014) · Nature reviews. Immunology · doi:10.1038/nri3707 · Cited by 1,585 · see citing works
Sutton, C. E., Lalor, S. J., Sweeney, C. M., Brereton, C. F., Lavelle, E. C., & Mills, K. H. G. (2009) · Immunity · doi:10.1016/j.immuni.2009.08.001 · Cited by 1,553 · see citing works
Structure and signalling in the IL-17 receptor family
Gaffen, S. L. (2009) · Nature reviews. Immunology · doi:10.1038/nri2586 · Cited by 1,475 · see citing works
Interleukin-17 and Type 17 Helper T Cells
Miossec, P., Korn, T., & Kuchroo, V. K. (2009) · New England Journal of Medicine · doi:10.1056/nejmra0707449 · Cited by 1,409 · see citing works
CD4 <sup>+</sup> T Cells: Differentiation and Functions
Luckheeram, R. V., Zhou, R., Verma, A. D., & Xia, B. (2012) · Clinical and Developmental Immunology · doi:10.1155/2012/925135 · Cited by 1,381 · see citing works
Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome
Milner, J. D., Brenchley, J. M., Laurence, A., Freeman, A. F., Hill, B. J., Elias, K. M., Kanno, Y., Spalding, C., Elloumi, H. Z., Paulson, M. L., et al. (2008) · Nature · doi:10.1038/nature06764 · Cited by 1,157 · see citing works
ATP drives lamina propria TH17 cell differentiation
Atarashi, K., Nishimura, J., Shima, T., Umesaki, Y., Yamamoto, M., Onoue, M., Yagita, H., Ishii, N., Evans, R., Honda, K., et al. (2008) · Nature · doi:10.1038/nature07240 · Cited by 1,089 · see citing works
TH17 cells in development: an updated view of their molecular identity and genetic programming
Dong, C. (2008) · Nature reviews. Immunology · doi:10.1038/nri2295 · Cited by 1,064 · see citing works
Self-citationLate Developmental Plasticity in the T Helper 17 Lineage
Lee, Y. K., Turner, H., Maynard, C. L., Oliver, J. R., Chen, D., Elson, C. O., & Weaver, C. T. (2009) · Immunity · doi:10.1016/j.immuni.2008.11.005 · Cited by 1,053 · see citing works
Ishigame, H., Kakuta, S., Nagai, T., Kadoki, M., Nambu, A., Komiyama, Y., Fujikado, N., Tanahashi, Y., Akitsu, A., Kotaki, H., et al. (2009) · Immunity · doi:10.1016/j.immuni.2008.11.009 · Cited by 1,004 · see citing works
Multiple sclerosis: a complicated picture of autoimmunity
McFarland, H. F., & Martin, R. (2007) · Nature Immunology · doi:10.1038/ni1507 · Cited by 985 · see citing works
Regulation of the immune response by the aryl hydrocarbon receptor
Gutiérrez-Vázquez, C., & Quintana, F. J. (2018) · Immunity · doi:10.1016/j.immuni.2017.12.012 · Cited by 985 · see citing works
Volpe, E., Servant, N., Zollinger, R., Bogiatzi, S. I., Hupé, P., Barillot, E., & Soumelis, V. (2008) · Nature Immunology · doi:10.1038/ni.1613 · Cited by 938 · see citing works
Martin, B., Hirota, K., Cua, D. J., Stockinger, B., & Veldhoen, M. (2009) · Immunity · doi:10.1016/j.immuni.2009.06.020 · Cited by 822 · see citing works
Regulation of inflammatory responses by IL-17F
Yang, X. O., Chang, S. H., Park, H., Nurieva, R., Shah, B., Acero, L., Wang, Y.-H., Schluns, K. S., Broaddus, R. R., Zhu, Z., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071978 · Cited by 739 · see citing works
Self-citationIL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice
Cho, J. S., Pietras, E. M., Garcia, N. C., Ramos, R. I., Farzam, D. M., Monroe, H. R., Magorien, J. E., Blauvelt, A., Kolls, J. K., Cheung, A. L., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40891 · Cited by 658 · see citing works
Deficiency of Th17 cells in hyper IgE syndrome due to mutations in <i>STAT3</i>
Ma, C. S., Chew, G. Y. J., Simpson, N., Priyadarshi, A., Wong, M., Grimbacher, B., Fulcher, D. A., Tangye, S. G., & Cook, M. C. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20080218 · Cited by 652 · see citing works
The Role of IL-17 and related cytokines in inflammatory autoimmune diseases
Kuwabara, T., Ishikawa, F., Kondo, M., & Kakiuchi, T. (2017) · Mediators of Inflammation · doi:10.1155/2017/3908061 · Cited by 519 · 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
Wang, Y.-H., Voo, K. S., Liu, B., Chen, C.-Y., Uygungil, B., Spoede, W., Bernstein, J. A., Huston, D. P., & Liu, Y.-J. (2010) · Journal of Experimental Medicine · doi:10.1084/jem.20101376 · Cited by 431 · see citing works
How do immune cells overcome the blood-brain barrier in multiple sclerosis?
Larochelle, C., Alvarez, J. I., & Prat, A. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.04.066 · Cited by 405 · see citing works
Gaffen, S. L., & Hajishengallis, G. (2008) · Journal of Dental Research · doi:10.1177/154405910808700908 · Cited by 334 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“STAT3 is also essential for Th17 differentiation mediated by IL-6/transforming growth factor (TGF)-b/IL-21 (Laurence et al., 2007; Nurieva et al., 2007; Yang et al., 2007b; Zhou et al., 2007) and by IL-23/STAT3 (Ivanov et al., 2006; Yang et al., 2008b; Gaffen, 2009, 2011).”
BackgroundGenomic views of STAT function in CD4+ T helper cell differentiation
O'Shea, J. J., Lahesmaa, R., Vahedi, G., Laurence, A., & Kanno, Y. (2011) · Nature Reviews Immunology · doi:10.1038/nri2958 · Cited by 295 · see citing works
Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders.
Fasching, P., Stradner, M., Graninger, W., Dejaco, C., & Fessler, J. (2017) · Molecules · doi:10.3390/molecules22010134 · Cited by 254 · see citing works
Lubberts, E. (2010) · Seminars in Immunopathology · doi:10.1007/s00281-009-0189-9 · Cited by 173 · see citing works
Type 1 regulatory T cells (Tr1) in autoimmunity
Pot, C., Apetoh, L., & Kuchroo, V. K. (2011) · Seminars in Immunology · doi:10.1016/j.smim.2011.07.005 · Cited by 171 · see citing works
Yin–Yang of costimulation: crucial controls of immune tolerance and function
Nurieva, R. I., Liu, X., & Dong, C. (2009) · Immunological Reviews · doi:10.1111/j.1600-065x.2009.00769.x · Cited by 157 · see citing works
Self-citationSlyepchenko, A., Maes, M., Köhler, C. A., Anderson, G., Quevedo, J., Alves, G. S., Berk, M., Fernandes, B. S., & Carvalho, A. F. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.002 · Cited by 89 · see citing works
Signal transduction and Th17 cell differentiation
O'Shea, J. J., Steward-Tharp, S. M., Laurence, A., Watford, W. T., Wei, L., Adamson, A. S., & Fan, S. (2009) · Microbes and Infection · doi:10.1016/j.micinf.2009.04.007 · Cited by 73 · see citing works
Th17 cell pathogenicity in autoimmune disease
Park, E., & Ciofani, M. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-025-01535-9 · Cited by 75 · see citing works
Induction of a colitogenic phenotype in Th1-like cells depends on interleukin-23 receptor signaling
Pawlak, M., DeTomaso, D., Schnell, A., Meyer zu Horste, G., Lee, Y., Nyman, J., Dionne, D., Regan, B. M. L., Singh, V., Delorey, T., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.08.007 · Cited by 49 · see citing works
Kaplan, M. H., Glosson, N. L., Stritesky, G. L., Yeh, N., Kinzfogl, J., Rohrabaugh, S. L., Goswami, R., Pham, D., Levy, D. E., Brutkiewicz, R. R., et al. (2011) · Blood · doi:10.1182/blood-2011-02-334367 · Cited by 41 · see citing works
- Authors
- Nurieva, R., Yang, X. O., Martinez, G., Zhang, Y., Panopoulos, A. D., Ma, L., Schluns, K., Tian, Q., Watowich, S. S., Jetten, A. M., & Dong, C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Institute for Systems Biology (US)
- National Institutes of Health (US)
- Corresponding author
- Nurieva, Roza
- Dong, Chen
- ORCID
- Venue
- Nature
- Published
- 2007-06-20
- Volume
- 448
- Issue
- 7152
- Pages
- 480-483
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2155013311
- Cited by
- 1,466
- References
- 4
- Citations by year
- 2026: 25 · 2025: 20 · 2024: 19 · 2023: 40 · 2022: 39 · 2021: 47 · 2020: 39 · 2019: 53 · 2018: 53 · 2017: 68 · 2016: 62 · 2015: 83 · 2014: 88 · 2013: 90 · 2012: 96
- FWCI
- 61.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- IL-21, autocrine cytokine signaling, T cell differentiation, STAT3, RORγ, Foxp3, interleukin-6, experimental autoimmune encephalomyelitis, inflammatory T cells, IL-23, RORC
- MeSH terms
- Interleukin-21, Animals, Cell Differentiation, Gene Expression Regulation, T-Lymphocytes, Helper-Inducer, Inflammation, Interleukins, Lymphocyte Activation, Receptors, Thyroid Hormone, Interleukin-6, Receptors, Retinoic Acid, Autocrine Communication, Interleukin-17, STAT3 Transcription Factor, Mice, Forkhead Transcription Factors, Nuclear Receptor Subfamily 1, Group F, Member 3
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
