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- Title
An autoimmune transcriptional circuit drives FOXP3<sup>+</sup> regulatory T cell dysfunction.
- Authors
Sumida, Tomokazu S.; Lincoln, Matthew R.; He, Liang; Park, Yongjin; Ota, Mineto; Oguchi, Akiko; Son, Raku; Yi, Alice; Stillwell, Helen A.; Leissa, Greta A.; Fujio, Keishi; Murakawa, Yasuhiro; Kulminski, Alexander M.; Epstein, Charles B.; Bernstein, Bradley E.; Kellis, Manolis; Hafler, David A.
- Abstract
Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs 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 Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs 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 Treg 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 Tregs in autoimmune diseases. Editor's summary: Regulatory T cells (Tregs) are known to be dysfunctional in autoimmune diseases, but the cause of this dysfunction has not been fully elucidated. Here, Sumida et al. found that Tregs isolated from individuals with multiple sclerosis, an autoimmune disease of the central nervous system, had increased expression of the short isoform of PR domain zinc finger protein 1 (PRDM1-S), which destabilized expression of the essential Treg transcription factor FOXP3 and induced Treg dysfunction mediated through SGK1, a salt-sensing kinase. Upstream epigenetic analysis revealed a regulatory role for AP-1 and IRF transcription factors in this circuit. The authors detected similar up-regulation of PRDM1-S in other autoimmune diseases, suggesting that PRDM1-S overexpression may be a common feature of Treg dysfunction. —Courtney Malo
- Subjects
INTERFERON regulatory factors; REGULATORY T cells; ZINC-finger proteins; AP-1 transcription factor; CENTRAL nervous system diseases; TRANSCRIPTION factors
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 762, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adp1720