An autoimmune transcriptional circuit drives FOXP3 <sup>+</sup> regulatory T cell dysfunction-Reference-Cited by-同舟云学术

An autoimmune transcriptional circuit drives FOXP3 ⁺ regulatory T cell dysfunction

Published:2024-08-28 Issue:762 Volume:16 Page:
ISSN:1946-6234
Container-title:Science Translational Medicine
language:en
Short-container-title:Sci. Transl. Med.

Author:

Sumida Tomokazu S.¹²^ORCID,Lincoln Matthew R.¹²³⁴^ORCID,He Liang²⁵⁶^ORCID,Park Yongjin²⁵^ORCID,Ota Mineto⁷^ORCID,Oguchi Akiko⁸⁹^ORCID,Son Raku⁸⁹^ORCID,Yi Alice¹^ORCID,Stillwell Helen A.¹^ORCID,Leissa Greta A.¹^ORCID,Fujio Keishi⁷^ORCID,Murakawa Yasuhiro⁸⁹^ORCID,Kulminski Alexander M.⁶^ORCID,Epstein Charles B.²^ORCID,Bernstein Bradley E.²¹⁰^ORCID,Kellis Manolis²⁵^ORCID,Hafler David A.¹²^ORCID

Affiliation:

1. Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.

2. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.

3. Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M6R 1B5, Canada.

4. Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, ON M6R 1B5, Canada.

5. Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge, MA 02139, USA.

6. Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27705, USA.

7. Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.

8. RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.

9. Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8303, Japan.

10. Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.

Abstract

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4 + FOXP3 + regulatory T cells (T regs ) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T regs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1 , which led to destabilization of forkhead box P3 (FOXP3) and T reg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T regs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and T reg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T regs in autoimmune diseases.

Publisher

American Association for the Advancement of Science (AAAS)

Link

https://www.science.org/doi/pdf/10.1126/scitranslmed.adp1720

Reference118 articles.

1. Systematic Localization of Common Disease-Associated Variation in Regulatory DNA

2. The cis-Regulatory Atlas of the Mouse Immune System

3. Genetic and epigenetic fine mapping of causal autoimmune disease variants

4. Dynamic Response Genes in CD4+ T Cells Reveal a Network of Interactive Proteins that Classifies Disease Activity in Multiple Sclerosis

5. No differential gene expression for CD4(+) T cells of MS patients and healthy controls;Brorson I. S.;Mult. Scler. J. Exp. Transl. Clin.,2019