Journal Article
. 2020 May; 52(6):1119-1132.e4.
doi: 10.1016/j.immuni.2020.04.006.

Regulatory T Cell-Specific Epigenomic Region Variants Are a Key Determinant of Susceptibility to Common Autoimmune Diseases

Naganari Ohkura 1 Yoshiaki Yasumizu 2 Yohko Kitagawa 3 Atsushi Tanaka 1 Yamami Nakamura 3 Daisuke Motooka 4 Shota Nakamura 4 Yukinori Okada 5 Shimon Sakaguchi 6 
Affiliations
  • PMID: 32362325
  •     24 citations

Abstract

The contribution of FOXP3-expressing naturally occurring regulatory T (Treg) cells to common polygenic autoimmune diseases remains ambiguous. Here, we characterized genome-wide epigenetic profiles (CpG methylation and histone modifications) of human Treg and conventional T (Tconv) cells in naive and activated states. We found that single-nucleotide polymorphisms (SNPs) associated with common autoimmune diseases were predominantly enriched in CpG demethylated regions (DRs) specifically present in naive Treg cells but much less enriched in activation-induced DRs common in Tconv and Treg cells. Naive Treg cell-specific DRs were largely included in Treg cell-specific super-enhancers and closely associated with transcription and other epigenetic changes in naive and effector Treg cells. Thus, naive Treg cell-specific CpG hypomethylation had a key role in controlling Treg cell-specific gene transcription and epigenetic modification. The results suggest possible contribution of altered function or development of natural Treg cells to the susceptibility to common autoimmune diseases.

Keywords: CD25; CTLA-4; DNA methylation; FoxP3; SNPs; autoimmune diseases; epigenome; genetic susceptibility; regulatory T cells; super-enhancer.

Transcriptional and epigenetic basis of Treg cell development and function: its genetic anomalies or variations in autoimmune diseases.
Naganari Ohkura, Shimon Sakaguchi.
Cell Res, 2020 May 06; 30(6). PMID: 32367041    Free PMC article.
Review.
Functional CRISPR dissection of gene networks controlling human regulatory T cell identity.
Kathrin Schumann, Siddharth S Raju, +18 authors, Alexander Marson.
Nat Immunol, 2020 Sep 30; 21(11). PMID: 32989329    Free PMC article.
Maintenance DNA methylation is essential for regulatory T cell development and stability of suppressive function.
Kathryn A Helmin, Luisa Morales-Nebreda, +9 authors, Benjamin D Singer.
J Clin Invest, 2020 Sep 09; 130(12). PMID: 32897881    Free PMC article.
Epigenetics of the antibody and autoantibody response.
Justin B Moroney, Daniel P Chupp, +2 authors, Paolo Casali.
Curr Opin Immunol, 2020 Nov 12; 67. PMID: 33176228    Free PMC article.
Review.
Genetics Meets Epigenetics in Treg Cells and Autoimmunity.
Paula A Agudelo Garcia, Shelley L Berger.
Immunity, 2020 Jun 20; 52(6). PMID: 32553177    Free PMC article.
Thymus and autoimmunity.
Alexander Marx, Yosuke Yamada, +4 authors, Cleo-Aron Weis.
Semin Immunopathol, 2021 Feb 05; 43(1). PMID: 33537838    Free PMC article.
Review.
Lower Functional and Proportional Characteristics of Cord Blood Treg of Male Newborns Compared with Female Newborns.
Viktor Černý, Olga Novotná, +5 authors, Jiří Hrdý.
Biomedicines, 2021 Feb 13; 9(2). PMID: 33572097    Free PMC article.
Genomics-driven drug discovery based on disease-susceptibility genes.
Kyuto Sonehara, Yukinori Okada.
Inflamm Regen, 2021 Mar 12; 41(1). PMID: 33691789    Free PMC article.
Review.
Aging imparts cell-autonomous dysfunction to regulatory T cells during recovery from influenza pneumonia.
Luisa Morales-Nebreda, Kathryn A Helmin, +7 authors, Benjamin D Singer.
JCI Insight, 2021 Feb 19; 6(6). PMID: 33600379    Free PMC article.
Epigenetic Modifiers: Anti-Neoplastic Drugs With Immunomodulating Potential.
Ken Maes, Anna Mondino, +4 authors, Karine Breckpot.
Front Immunol, 2021 Apr 17; 12. PMID: 33859645    Free PMC article.
Review.
Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance.
Guo-Hua Li, Qiang Qu, +5 authors, Jian Qu.
J Exp Clin Cancer Res, 2021 May 21; 40(1). PMID: 34011395    Free PMC article.
Review.
Taking regulatory T cells into medicine.
Shimon Sakaguchi.
J Exp Med, 2021 May 27; 218(6). PMID: 34037676    Free PMC article.
Regulatory T Cells-Related Genes Are under DNA Methylation Influence.
Magdalena Piotrowska, Mateusz Gliwiński, Piotr Trzonkowski, Dorota Iwaszkiewicz-Grzes.
Int J Mol Sci, 2021 Jul 21; 22(13). PMID: 34281195    Free PMC article.
Review.
Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes.
Maria Bettini, Matthew L Bettini.
Diabetes, 2021 May 22; 70(6). PMID: 34016597    Free PMC article.
Review.
Metabolic Controls on Epigenetic Reprogramming in Regulatory T Cells.
Jingli Lu, Yan Liang, +3 authors, Chengliang Zhang.
Front Immunol, 2021 Aug 24; 12. PMID: 34421930    Free PMC article.
Review.
Sirtuin 1, Visfatin and IL-27 Serum Levels of Type 1 Diabetic Females in Relation to Cardiovascular Parameters and Autoimmune Thyroid Disease.
Magdalena Łukawska-Tatarczuk, Edward Franek, +6 authors, Beata Mrozikiewicz-Rakowska.
Biomolecules, 2021 Aug 28; 11(8). PMID: 34439776    Free PMC article.
Prenatal cadmium exposure does not induce greater incidence or earlier onset of autoimmunity in the offspring.
Jamie L McCall, Harry C Blair, +3 authors, John B Barnett.
PLoS One, 2021 Sep 04; 16(9). PMID: 34478449    Free PMC article.
Transcriptional Changes in Regulatory T Cells From Patients With Autoimmune Polyendocrine Syndrome Type 1 Suggest Functional Impairment of Lipid Metabolism and Gut Homing.
Amund Holte Berger, Eirik Bratland, +7 authors, Anette Susanne Bøe Wolff.
Front Immunol, 2021 Sep 17; 12. PMID: 34526996    Free PMC article.
Leveraging diet to engineer the gut microbiome.
Mathis Wolter, Erica T Grant, +4 authors, Mahesh S Desai.
Nat Rev Gastroenterol Hepatol, 2021 Sep 29; 18(12). PMID: 34580480
Review.
T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives.
Fabiana Corsi-Zuelli, Bill Deakin, +5 authors, Cristina Marta Del-Ben.
Brain Behav Immun Health, 2021 Oct 19; 17. PMID: 34661175    Free PMC article.
Strong Expansion of Human Regulatory T Cells for Adoptive Cell Therapy Results in Epigenetic Changes Which May Impact Their Survival and Function.
Kristy Ou, Dania Hamo, +13 authors, Julia K Polansky.
Front Cell Dev Biol, 2021 Dec 07; 9. PMID: 34869339    Free PMC article.
CCR8-targeted specific depletion of clonally expanded Treg cells in tumor tissues evokes potent tumor immunity with long-lasting memory.
Yujiro Kidani, Wataru Nogami, +39 authors, Shimon Sakaguchi.
Proc Natl Acad Sci U S A, 2022 Feb 11; 119(7). PMID: 35140181    Free PMC article.
The link between circulating follicular helper T cells and autoimmunity.
Lucy S K Walker.
Nat Rev Immunol, 2022 Mar 13;. PMID: 35277664    Free PMC article.
Review.
Multiple sclerosis genetic and non-genetic factors interact through the transient transcriptome.
Renato Umeton, Gianmarco Bellucci, +10 authors, Giovanni Ristori.
Sci Rep, 2022 May 10; 12(1). PMID: 35534508    Free PMC article.