Egr-1 gene identified as crucial regulator of regulatory T cells in multiple sclerosis

Autoimmune diseases, such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and rheumatoid arthritis (RA), affect millions of people worldwide. These conditions arise when the body's immune system fails to distinguish between "self" and "foreign" cells, and mistakenly attacks its own healthy cells, resulting in persistent inflammation and tissue damage. Central to these autoimmune responses are CD4⁺ T cells, a class of immune cells that can either promote or suppress the condition.

Regulatory T cells (T_reg) are a special subtype of CD4⁺ T cells that act as the immune system's peacekeepers. T_reg cells, marked by protein Foxp3, help in suppressing harmful immune responses. However, when the function of T_reg cells is compromised, as seen in cases of MS and IBD, the immune response is dominated by the Th1 and Th17 cells (other CD4⁺T cell subtypes), which promote inflammation, further worsening the disease symptoms. Therefore, boosting the development and activity of T_reg cells is emerging as a promising therapeutic approach, but the mechanisms underlying its effective regulation remain unclear.

In pursuit of a deeper understanding of these mechanisms, a team of Chinese scientists led by Dr. Xiaojun Wu and Dr. Fei Huang from the Shanghai Key Laboratory of Compound Chinese Medicines, SHUTCM, China, and Dr. Weidong Pan from the Department of Neurology, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China, explored the role of Early Growth Response Gene 1 (Egr-1) in promoting the activity of T_reg cells. The study was conducted in a well-established animal model of MS, called experimental autoimmune encephalomyelitis (EAE), to confirm the mechanisms. The findings of this study were published in Volume 8 of Research on April 15, 2025.

Elaborating more, Dr. Wu, the lead author of this study, says "We started by screening the genes that appeared different between mice with mild and severe EAE." Further, he adds, "Among the top identified genes in CD4⁺ T cells, Egr-1 stood out as significantly downregulated in severe disease."

After identifying Egr-1 as a regulatory gene, the team assessed its role by using genetically engineered mice lacking Egr-1 in CD4⁺ T cells. These mice were induced with EAE and tracked for disease progression. The researchers also analyzed the immune cell compositions in the spleen, lymph nodes, and central nervous system of these mice.

"The mice lacking Egr-1 showed worse disease, fewer T_reg cells, and more inflammatory TH17 and TH1 cells" explains Dr. Huang.

The researchers also conducted additional in vitro experiments. By analyzing isolated human CD4⁺ T cells from MS patients and healthy donors, they confirmed that both Egr-1 and Foxp3 levels were reduced in patient samples. Further, to determine whether Egr-1 directly regulates Foxp3, the researchers used chromatin immunoprecipitation, which revealed that Egr-1 binds to the Foxp3 promoter. Additionally, using luciferase reporter assays, they also confirmed that Egr-1 binding increases Foxp3 gene activity. They then traced the pathway to TGF-β (Transforming Growth Factor Beta) signaling via the Raf/Mek/Erk cascade, which activates Egr-1.

"We identified a unique mechanism of Egr-1," explains Dr. Pan, "First, TGF-β activates the Raf/Mek/Erk cascade, which activates Egr-1. Egr-1 then directly binds to the Foxp3 promoter to enhance its expression, bypassing the classical Smad3-dependent pathway."

What's more, the researchers also investigated the effect of a natural compound, Calycosin, which acts as an Egr-1 agonist. Treatment with calycosin restored T_reg cell functions and improve clinical outcomes in mice with EAE, but only in those with functional Egr-1.

Overall, the study underscores the essential role of Egr-1 in T_reg cell development and function, identifying it as a central molecular switch in immune regulation. By elucidating its mechanism and validating the effect of a natural Egr-1 agonist, the study suggests that targeting Egr-1 may offer a promising treatment strategy, potentially transforming therapeutic approaches to autoimmune diseases.