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Transcriptional and Epigenetic Control of T Helper Cell Specification: Molecular Mechanisms Underlying Commitment and Plasticity
Open accessAbstract
T helper cell differentiation occurs in the context of the extracellular cytokine milieu evoked by diverse microbes and other pathogenic stimuli along with T cell receptor stimulation. The culmination of these signals results in specification of T helper lineages, which occurs through the combinatorial action of multiple transcription factors that establish distinctive transcriptomes. In this manner, inducible, but constitutively active, master regulators work in conjunction with factors such as the signal transducer and activator of transcriptions (STATs) that sense the extracellular environment. The acquisition of a distinctive transcriptome also depends on chromatin modifications that impact key cis elements as well as the changes in global genomic organization. Thus, signal transduction and epigenetics are linked in these processes of differentiation. In this review, recent advances in understanding T helper lineage specification and deciphering the action of transcription factors are summarized with emphasis on comprehensive views of the dynamic T cell epigenome.
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“Differentiation of T cells to specific TH lineages is driven by specific transcription factors but reinforced by epigenetic modifications on histone tails (H3K4 and H3K27 trimethylation) and DNA methylation of CpG dinucleotides (103).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [103]
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ResultTonic LAT-HDAC7 Signals Sustain Nur77 and Irf4 Expression to Tune Naive CD4 T Cells
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Histone demethylases UTX and JMJD3 are required for NKT cell development in mice
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“This is in contrast to Th cell differentiation, where epigenetic changes at lineage-specific genes have been well documented (36).”
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“Emerging data also are showing a role for epigenetic regulation of the polarisation of other T-cell subsets including Th17 cells and regulatory T cells (Treg) (McAleer & Kolls 2011; Kanno et al. 2012).”
BackgroundEx Vivo Signaling Protein Mapping in T Lymphocytes in the Psoriatic Arthritis Joints
Fiocco, U., Martini, V., Accordi, B., Caso, F., Costa, L., Oliviero, F., Scanu, A., Felicetti, M., Frallonardo, P., Facco, M., et al. (2015) · Journal of Rheumatology Supplement · doi:10.3899/jrheum.150636 · Cited by 34
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A cohesin–OCT4 complex mediates Sox enhancers to prime an early embryonic lineage
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“Chromosomal translocations present in lymphoid malignancies will (1) remove CTCF sites close to the oncogenes, (2) bring in enhancer-associated CTCF sites, or (3) dramatically alter the spacing between CTCF sites and their cognate genes.”
BackgroundResultTET proteins in natural and induced differentiation
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BackgroundCD4+ T Cell Differentiation in Infection: Amendments to the Th1/Th2 Axiom
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“These studies hint that there may be other factors controlling IL-12-induced Th1 development that are independent of T-bet and STAT4 itself, although to date, none have been found [13, 14].”
BackgroundEpigenetic Regulation in the Pathogenesis of Sjögren Syndrome and Rheumatoid Arthritis
Ibáñez-Cabellos, J. S., Seco-Cervera, M., Osca-Verdegal, R., Pallardó, F. V., & García‐Giménez, J. L. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.01104 · Cited by 28
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 29
Kumagai, J., Kiuchi, M., Kokubo, K., Yagyu, H., Nemoto, M., Tsuji, K., Nagahata, K., Sasaki, A., Hishiya, T., Onoue, M., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2302903120 · Cited by 29
“STAT family members are key players in the differentiation of certain helper T cell subsets (35).”
BackgroundSelf-citationEpigenetics of T cells regulated by Polycomb/Trithorax molecules
Onodera, A., & Nakayama, T. (2015) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2015.03.001 · Cited by 27
Omar, H. A., & Tolba, M. F. (2019) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2019.01.009 · Cited by 28
Role of Tet2 in Regulating Adaptive and Innate Immunity
Li, J., Li, L., Sun, X., Deng, T., Huang, G., Li, X., Xie, Z., & Zhou, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.665897 · Cited by 26
“The Foxp3 locus contains conserved CpG-rich regions called Treg-specific demethylated regions (TSDRs), and CNS2 was the original TSDR found in this region (Kanno et al., 2012).”
BackgroundDefining the molecular blueprint that drives CD8+ T cell differentiation in response to infection
Russ, B. E., Denton, A. E., Hatton, L. A., Croom, H. A., Olson, M. R., & Turner, S. (2012) · Front. Immun. · doi:10.3389/fimmu.2012.00371 · Cited by 31
“There is a large body of work has determined that specific epigenetic mechanisms underpin CD4+ effector T cell lineage commitment from a naïve state into different effector subsets (reviewed by Ansel et al., 2003; Kanno et al., 2012).”
BackgroundAge-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus
Krenzien, F., Quante, M., Heinbokel, T., Seyda, M., Minami, K., Uehara, H., Biefer, H. R. C., Schuitenmaker, J. M., Gabardi, S., Splith, K., et al. (2016) · American Journal of Transplantation · doi:10.1111/ajt.14087 · Cited by 27
“Age-dependent effects on Ca/calmodulindependent calcineurin activity by TAC Next, we assessed Ca influx and calcineurin levels, both known to play a central role in nuclear factor of activated Tcells (NFAT) activation, a major downstream pathway of T cell receptor activation (27).”
BackgroundDifferential T ‐cell receptor signals for T helper cell programming
Morel, P. A. (2018) · Immunology · doi:10.1111/imm.12945 · Cited by 28
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
Genetic variation associated with cardiovascular risk in autoimmune diseases
Perrotti, P. P., Aterido, A., Fernández‐Nebro, A., Cañete, J. D. D., Ferrándiz, C., Tornero, J., Gisbert, J. P., Domènech, E., Fernández‐Gutiérrez, B., Gomollón, F., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185889 · Cited by 27
Spatial regulation of IL-4 signalling in vivo
Redpath, S. A., Heieis, G. A., & Perona‐Wright, G. (2015) · Cytokine · doi:10.1016/j.cyto.2015.02.026 · Cited by 26
Epigenetic regulation of T helper cells and intestinal pathogenicity
Hagihara, Y., Yoshimatsu, Y., Mikami, Y., Takada, Y., Mizuno, S., & Kanai∥, T. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00732-9 · Cited by 25
Sun, Y., Deng, W., Yao, G., Chen, W., Tang, X., Feng, X., Lu, L., & Sun, L. (2018) · Clinical Immunology · doi:10.1016/j.clim.2018.01.008 · Cited by 25
Systems Approaches towards Molecular Profiling of Human Immunity
Burel, J. G., Apte, S. H., & Doolan, D. L. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.11.006 · Cited by 25
“Also, epigenetic signatures in signal transducer and activator of transcription (STAT) promoters have been implicated in controlling T helper cell differentiation, suggesting that drugs that specifically target epigenetic modifications may direct the fate and cytokine capacity of T cells [30].”
BackgroundSekiya, T., Kagawa, S., Masaki, K., Fukunaga, K., Yoshimura, A., & Τακακι, S. (2021) · iScience · doi:10.1016/j.isci.2021.102166 · Cited by 25
Riou, C., Strickland, N., Soares, A. P., Corleis, B., Kwon, D. S., Wherry, E. J., Wilkinson, R. J., & Burgers, W. A. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1502094 · Cited by 24
Elimination of CD4lowHLA-G+ T cells overcomes castration-resistance in prostate cancer therapy
Wang, C., Chen, J., Zhang, Q., Li, W., Zhang, S., Xu, Y., Wang, F., Zhang, B., Zhang, Y., & Gao, W. (2018) · Cell Research · doi:10.1038/s41422-018-0089-4 · Cited by 25
Kiuchi, M., Onodera, A., Kokubo, K., Ichikawa, T., Morimoto, Y., Kawakami, E., Takayama, N., Eto, K., Koseki, H., Hirahara, K., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20201690 · Cited by 22
Self-citationγδ T cells license immature B cells to produce a broad range of polyreactive antibodies
Rampoldi, F., Donato, E., Ullrich, L., Deseke, M., Janssen, A., Demera, A., Sandrock, I., Bubke, A., Juergens, A.-L., Swallow, M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110854 · Cited by 22
Radtke, D., Lacher, S. M., Szumilas, N., Sandrock, L., Ackermann, J. A., Nitschke, L., & Zinser, E. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501764 · Cited by 22
“Finally, induced regulatory T cells (Tregs) can be induced to inhibit immune responses (11, 12).”
BackgroundExpanding Diversity and Common Goal of Regulatory T and B Cells. I: Origin, Phenotype, Mechanisms
Bocian, K., Kiernozek, E., Domagala-Kulawik, J. J., Korczak-Kowalska, G., Stelmaszczyk‐Emmel, A., & Drela, N. (2017) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-017-0469-3 · Cited by 24
“Recently, it has been shown that allergies, tumors, and many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), are caused by deregulation of epigenetic mechanisms in Treg cells (Cuddapah et al. 2010; Kanno et al. 2012).”
BackgroundNematode ascarosides attenuate mammalian type 2 inflammatory responses
Shinoda, K., Choe, A., Hirahara, K., Kiuchi, M., Kokubo, K., Ichikawa, T., Hoki, J. S., Suzuki, A., Bose, N., Appleton, J. A., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2108686119 · Cited by 23
Self-citationTranscriptional and Epigenetic Regulation of Context-Dependent Plasticity in T-Helper Lineages
Friedman, M. J., Lee, H., Lee, J., & Oh, S. (2023) · Immune Network · doi:10.4110/in.2023.23.e5 · Cited by 22
“These results support prior in vitro research indicating that signature cytokines of a particular Th subset are highly repressed in other subtypes but also underscore the regulatory complexity of CD4+ T cell lineages and their potential for interconversion (41,49).”
BackgroundResultDifferentiation and regulation of CD4+ T cell subsets in Parkinson’s disease
Sun, X., Gu, R., & Bai, J. (2024) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-024-05402-0 · Cited by 23
“…IL-12 secreted by APCs and IFN-γ produced by NK cells activate the transcription factors signal transducer and activator of transcription 4 (STAT4) and STAT1, respectively, which further induce T-box expressed in T cells (T-bet) expression, thereby promoting Th1 cell polarization [28, 29] (Fig.”
BackgroundOnabajo, O. O., & Mattapallil, J. J. (2014) · Current HIV Research · doi:10.2174/1570162x12666140225153552 · Cited by 22
Epigenetics and the IRFs: A complex interplay in the control of immunity and autoimmunity
Rogatsky, I., Chandrasekaran, U., Manni, M., Yi, W., & Pernis, A. B. (2013) · Autoimmunity · doi:10.3109/08916934.2013.853050 · Cited by 20
“code) and of ‘‘readers’’ such as bromodomain-containing proteins (that bind to histone modifications and thus ‘‘read’’ the code) enables histone acetylation to become an integrating point for diverse sets of environmental cues and thus plays a fundamental role in the tight and dynamic control of gene expression [28,30…”
BackgroundRole of OCT-1 and partner proteins in T cell differentiation
Hwang, S. S., Kim, L. K., Lee, G. R., & Flavell, R. A. (2016) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2016.04.006 · Cited by 21
“Th2 cells express its master regulator GATA-3 and produce Th2 cytokines such as interleukin-4 (IL-4), IL-5 and IL-13; in such a way, Th2 cells function to stimulate B cell andmediated humoral immune response to eliminate parasitic worms [1,2].”
BackgroundThe tumor microenvironment disarms CD8+ T lymphocyte function via a miR-26a-EZH2 axis
Long, H., Xiang, T., Luo, J., Li, F., Lin, R., Liu, S.-Q., Jiang, S., Hu, C., Chen, G., Wong, E., et al. (2016) · OncoImmunology · doi:10.1080/2162402x.2016.1245267 · Cited by 21
Vincenzetti, L., Leoni, C., Chirichella, M., Kwee, I., & Monticelli, S. (2019) · European Journal of Immunology · doi:10.1002/eji.201847967 · Cited by 21
Modulation of dendritic cell function by Trichomonas vaginalis-derived secretory products
Song, M.-J., Lee, J.-J., Nam, Y. H., Kim, T., Chung, Y. W., Kim, M., Choi, Y., Shin, M. H., & Kim, H. (2015) · BMB Reports · doi:10.5483/bmbrep.2015.48.2.116 · Cited by 21
DNA methylation, bacteria and airway inflammation
Perez-Novo, C. A., & Bachert, C. (2014) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000130 · Cited by 22
“Moreover, it is known that regulation of T cell function is closely related to changes in the methylation pattern at the promoter region of the specific genes to induce the appropriate T-helper immune response [15].”
BackgroundCorreale, J. D., Marrodán, M., & Contentti, E. C. (2021) · Immunology · doi:10.1111/imm.13389 · Cited by 22
“After TCR rearrangements, T cells remain responsive to changing environments via epigenetic modifications that polarize CD4+ T cells into different phenotypic subsets [56].”
BackgroundProtein Kinase C θ Regulates the Phenotype of Murine CD4+ Th17 Cells
Wachowicz, K., Hermann‐Kleiter, N., Meisel, M., Siegmund, K., Thuille, N., & Baier, G. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096401 · Cited by 20
“pronounced plasticity between particular lineages exists [2].”
A Novel miR-24–TCF1 Axis in Modulating Effector T Cell Responses
Cho, S., Wu, C.-J., Nguyen, D. T., Lin, L.-L., Chen, M., Khan, A. A., Yang, B.-H., Fu, W., & Lu, L. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601404 · Cited by 22
“once cells are fully differentiated, although TCF1 could still modulate the production of effector cytokines, its impact on the expression of lineage-specific transcription factors diminishes because those molecules would be stabilized by many transcriptional and epigenetic regulations (25).”
Metabolism in Immune Cell Differentiation and Function
Chapman, N. M., Shrestha, S., & Chi, H. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-94-024-1170-6_1 · Cited by 22
Jahangard, L., & Behzad, M. (2020) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2020.577250 · Cited by 20
Metadata
- Authors
- Kanno, Y., Vahedi, G., Hirahara, K., Singleton, K., & O'Shea, J. J.
- Affiliations
- National Institutes of Health (US)
- Molecular Immunology and Inflammation Branch, National Institutes of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892;
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2012-04-23
- Volume
- 30
- Issue
- 1
- Pages
- 707-731
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- PMC
- PMC3314163
- OpenAlex
- W2095649879
- Cited by
- 342
- References
- 163
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 16 · 2021: 19 · 2020: 13 · 2019: 21 · 2018: 22 · 2017: 33 · 2016: 34 · 2015: 49 · 2014: 45 · 2013: 40 · 2012: 9
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99‐AA999999, Z99 AR999999, Z99 DA999999)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- T helper cell differentiation, transcription factors, chromatin modification, epigenetics, STAT signaling, T cell receptor signaling, cytokine signaling, T cell transcriptome, T cell plasticity, signal transduction
- MeSH terms
- Animals, Autoimmune Diseases, Cell Differentiation, Gene Expression Regulation, T-Lymphocytes, Helper-Inducer, Humans, Transcription Factors, Transcription, Genetic, Cell Lineage, RNA, Untranslated, Epigenesis, Genetic, Regulatory Elements, Transcriptional, Epigenomics
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