CoChat
Sign Up
Cited by 154T-cell and B-cell ImmunologyEpigenetics and DNA MethylationPsoriasis: Treatment and Pathogenesis

TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells

Open access
Tsagaratou, Ageliki, González-Avalos, Edahí, Rautio, Sini, Scott-Browne, James P, Togher, Susan, Pastor, William A, Rothenberg, Ellen V, Chavez, Lukas +2 more·2017·Nature Immunology
DOI 10.1038/ni.3630PMC PMC5376256
Open this paper in CoChat — free account

Abstract

TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR).

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/ni.3630

Cites

6 of 6 references verified0 citation errors · 0 not checkable

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.

A few free checks a day · papers already verified open instantly · results are public

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?

  • TET2 and TET3 are responsible for the development and proliferation of CD4+CD8+ double-positive thymocytes into invariant natural killer T cells (iNKT cells).

    “For instance, TET2 and TET3 are responsible for the development and proliferation of CD4+CD8+ double-positive thymocytes into invariant natural killer T cells (iNKT cells) (Tsagaratou et al., 2016).”

    From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Tsagaratou et al., 2016

    The Abstract reports that deleting Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes dysregulated iNKT-cell development and proliferation. It does not say that the double-positive thymocytes proliferate into iNKT cells; rather, TET proteins support proper iNKT development while suppressing aberrant iNKT-cell proliferation. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • TET2 plays important roles during the inflammatory response in different peripheral immune cells.

    “Recent reports have shown that TET2 plays important roles during the inflammatory response in different peripheral immune cells (Ichiyama et al., 2015)(Tsagaratou et al., 2016)(Zhang et al., 2015)(Cull et al., 2017).”

    From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Tsagaratou et al., 2016

    The Results (iNKT cell expansion; no page supplied) report expansion of iNKT cells in peripheral lymphoid organs after Tet2–Tet3 deletion. The Discussion (no page supplied) also says TET2 modulates cytokine production in CD4+ helper T cells. These passages support an immune-regulatory role, but this study primarily tests combined Tet2 and Tet3 loss and does not establish TET2 alone as regulating inflammatory responses across different peripheral immune cells. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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

Flagged first, then by citations

Research works printed but not linked: 49

  1. [1]Yui MA Rothenberg EV Developmental gene networks: a triathlon on the course to T cell identity Nat Rev Immunol 14 529 545 2014 25060579 PMC4153685
  2. [2]Carpenter AC Bosselut R Decision checkpoints in the thymus Nat Immunol 11 666 673 2010 20644572 PMC3388799
  3. [3]Bendelac A Savage PB Teyton L The biology of NKT cells Annu Rev Immunol 25 297 336 2007 17150027
  4. [4]Vahedi G Helper T-cell identity and evolution of differential transcriptomes and epigenomes Immunol Rev 252 24 40 2013 23405893 PMC3577092
  5. [5]Hogquist KA Jameson SC The self-obsession of T cells: how TCR signaling thresholds affect fate ‘decisions’ and effector function Nat Immunol 15 815 823 2014 25137456 PMC4348363
  6. [6]Lee YJ Holzapfel KL Zhu J Jameson SC Hogquist KA Steady-state production of IL-4 modulates immunity in mouse strains and is determined by lineage diversity of iNKT cells Nat Immunol 14 1146 1154 2013 24097110 PMC3824254
  7. [7]Winter DR Amit I The role of chromatin dynamics in immune cell development Immunol Rev 261 9 22 2014 25123274
  8. [8]Smith ZD Meissner A DNA methylation: roles in mammalian development Nat Rev Genet 14 204 220 2013 23400093
  9. [9]Tahiliani M Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1 Science 324 930 935 2009 19372391 PMC2715015
  10. [11]He YF Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA Science 333 1303 1307 2011 21817016 PMC3462231
  11. [13]Tsagaratou A Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation Proc Natl Acad Sci USA 111 E3306 E3315 2014 25071199 PMC4136618
  12. [14]Ko M Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2 Nature 468 839 843 2010 21057493 PMC3003755
  13. [15]Ko M Ten-Eleven-Translocation 2 (TET2) negatively regulates homeostasis and differentiation of hematopoietic stem cells in mice Proc Natl Acad Sci USA 108 14566 14571 2011 21873190 PMC3167529
  14. [16]Gu TP The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes Nature 477 606 610 2011 21892189
  15. [17]Lee YJ Jameson SC Hogquist KA Alternative memory in the CD8 T cell lineage Trends Immunol 32 50 56 2011 21288770 PMC3039080
  16. [18]Engel I Innate-like functions of natural killer T cell subsets result from highly divergent gene programs Nat Immunol 17 728 739 2016 27089380 PMC4944658
  17. [19]Yu S The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy Immunity 37 813 826 2012 23103132 PMC3501598
  18. [20]Karo JM Schatz DG Sun JC The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells Cell 159 94 107 2014 25259923 PMC4371485
  19. [21]Matthews JM Lester K Joseph S Curtis DJ LIM-domain-only proteins in cancer Nat Rev Cancer 13 111 122 2013 23303138
  20. [22]Ramsay RG Gonda TJ MYB function in normal and cancer cells Nat Rev Cancer 8 523 534 2008 18574464
  21. [23]Uddin MN Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival Proc Natl Acad Sci USA 113 7608 7613 2016 27330109 PMC4941433
  22. [24]Mathew R BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs Nature 491 618 621 2012 23086144 PMC3504649
  23. [25]Dose M Intrathymic proliferation wave essential for Valpha14+ natural killer T cell development depends on c-Myc Proc Natl Acad Sci USA 106 8641 8646 2009 19423665 PMC2689024
  24. [26]Carr T The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and TH2-type effector differentiation J Exp Med 212 793 807 2015 25897173 PMC4419352
  25. [28]Wolf E Lin CY Eilers M Levens DL Taming of the beast: shaping Myc-dependent amplification Trends Cell Biol 25 241 248 2014 25475704 PMC4380620
  26. [29]Lee YJ Lineage-specific effector signatures of invariant NKT cells are shared amongst γδ T, innate lymphoid, and TH cells J Immunol 197 1460 1470 2016 27385777 PMC4976040
  27. [30]Fonseca-Pereira D The neurotrophic factor receptor RET drives haematopoietic stem cell survival and function Nature 514 98 101 2014 25079320
  28. [31]Huang Y Pastor WA Zepeda-Martínez JA Rao A The anti-CMS technique for genome-wide mapping of 5-hydroxymethylcytosine Nat Protoc 7 1897 1908 2012 23018193 PMC3498982
  29. [33]Laurent L Dynamic changes in the human methylome during differentiation Genome Res 20 320 331 2010 20133333 PMC2840979
  30. [35]An J Acute loss of TET function results in aggressive myeloid cancer in mice Nat Commun 6 10071 2015 26607761 PMC4674670
  31. [36]Kieffer-Kwon KR Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation Cell 155 1507 1520 2013 24360274 PMC3905448
  32. [37]Lara-Astiaso D Immunogenetics. chromatin state dynamics during blood formation Science 345 943 949 2014 25103404 PMC4412442
  33. [38]Buenrostro JD Giresi PG Zaba LC Chang HY Greenleaf WJ Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position Nat Methods 10 1213 1218 2013 24097267 PMC3959825
  34. [39]Jeong M Large conserved domains of low DNA methylation maintained by Dnmt3a Nat Genet 46 17 23 2014 24270360 PMC3920905
  35. [40]Townsend MJ T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells Immunity 20 477 494 2004 15084276
  36. [41]Engel I Zhao M Kappes D Taniuchi I Kronenberg M The transcription factor Th-POK negatively regulates TH17 differentiation in Vα14i NKT cells Blood 120 4524 4532 2012 23034280 PMC3512232
  37. [42]Stritesky GL Jameson SC Hogquist KA Selection of self-reactive T cells in the thymus Annu Rev Immunol 30 95 114 2012 22149933 PMC3518413
  38. [43]Dobenecker MW Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation J Exp Med 212 297 306 2015 25687282 PMC4354372
  39. [44]Pereira RM Jarid2 is induced by TCR signaling and controls iNKT cell maturation Nat Commun 5 4540 2014 25105474 PMC4314221
  40. [46]Ichiyama K The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells Immunity 42 613 626 2015 25862091 PMC4956728
  41. [47]Sasidharan Nair V Song MH Oh KI Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner J Immunol 196 2119 2131 2016 26826239
  42. [48]Huang Y Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells Proc Natl Acad Sci USA 111 1361 1366 2014 24474761 PMC3910590
  43. [49]Ko M TET proteins and 5-methylcytosine oxidation in hematological cancers Immunol Rev 263 6 21 2015 25510268 PMC4617313
  44. [50]Lee PP A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival Immunity 15 763 774 2001 11728338
  45. [51]Heinen AP Improved method to retain cytosolic reporter protein fluorescence while staining for nuclear proteins Cytometry A 85 621 627 2014 24616430
  46. [52]Djuretic IM Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells Nat Immunol 8 145 153 2007 17195845
  47. [53]Picelli S Full-length RNA-seq from single cells using Smart-seq2 Nat Protoc 9 171 181 2014 24385147
  48. [54]Huang Y The behaviour of 5-hydroxymethylcytosine in bisulfite sequencing PLoS One 5 e8888 2010 20126651 PMC2811190
  49. [55]Tsagaratou A Rao A TET proteins and 5-methylcytosine oxidation in the immune system Cold Spring Harb Symp Quant Biol 78 1 10 2013 24619230 PMC4631521

Cited by

Sorted by citations

Authors
Tsagaratou, A., González-Avalos, E., Rautio, S., Scott-Browne, J. P., Togher, S., Pastor, W. A., Rothenberg, E. V., Chavez, L., Lähdesmäki, H., & Rao, A.
Affiliations
  • La Jolla Institute for Immunology (US)
  • Aalto University (FI)
  • California Institute of Technology (US)
Corresponding author
Rao, Anjana
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2016-11-21
Volume
18
Issue
1
Pages
45-53
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/ni.3630
PMC
PMC5376256
OpenAlex
W2552807099
Cited by
154
References
6
Citations by year
2026: 11 · 2025: 13 · 2024: 13 · 2023: 10 · 2022: 14 · 2021: 26 · 2020: 19 · 2019: 19 · 2018: 14 · 2017: 14 · 2016: 1
FWCI
9.70
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
  • National Institutes of Health (1s10od016262-01)
  • National Cancer Institute (R01CA151535, R35CA210043)
  • National Institute of Allergy and Infectious Diseases (R01AI044432)
  • National Center for Research Resources (S10RR027366)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
TET enzymes, TET2, TET3, invariant natural killer T cells, NKT17 cells, lineage specification, 5-methylcytosine, 5-hydroxymethylcytosine, DNA methylation, T cell development, RORγt, T-bet, ThPOK, CD1d, T cell receptor, lymphoproliferative disorders, chromatin accessibility
MeSH terms
T-bet Transcription Factor, Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Mice, Inbred C57BL, Proto-Oncogene Proteins, Receptors, Antigen, T-Cell, Transcription Factors, CD4 Antigens, CD8 Antigens, Mice, Knockout, Cell Lineage, DNA Methylation, T-Box Domain Proteins, Cell Proliferation, Dioxygenases, Mice, Precursor Cells, T-Lymphoid, Antigens, CD1d, Natural Killer T-Cells

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