Decoding Treatment Response: How Dimethyl Fumarate Targets Tc17 Cells in MS

Multiple sclerosis (MS) is a chronic autoimmune disease where the body’s own immune system attacks the central nervous system, leading to neurological symptoms, disability, and often, life-altering impacts—especially in young adults. While we’ve known that certain T cells (immune cells) play a role in this, the details have remained hazy. A new study published in Nature Communications sheds light on how a widely used MS drug, dimethyl fumarate (DMF), exerts its therapeutic effects—by suppressing a specific group of inflammatory CD8+ T cells known as Tc17 cells.

What Are Tc17 Cells, and Why Do They Matter?
In MS, the immune system mistakenly attacks myelin—the protective coating around nerve fibers. This attack is driven largely by T cells, a type of white blood cell. Among these, Tc17 cells—a subset of CD8+ T cells that produce the pro-inflammatory cytokine IL-17—have been found in high numbers in the brains and spinal cords of people with MS. Importantly, higher Tc17 counts correlate with worse symptoms, making them a compelling target for therapy.

Dimethyl Fumarate: More Than a Mystery Pill
DMF has been used for years to treat MS and psoriasis, but how it worked was not fully understood. We knew it had anti-inflammatory effects and boosted antioxidant responses, but the specifics—especially in T cells—were elusive.

This study finally connects the dots. Researchers tracked 36 MS patients before and after DMF therapy. Those who responded well to treatment (no disease activity after a year) had a significant drop in Tc17 cells. Interestingly, Th17 cells—the similar IL-17-producing CD4+ cells—were unaffected. This specificity hints at a focused mechanism of action.

How DMF Silences Tc17 Cells
The researchers found that DMF works by triggering oxidative stress inside Tc17 cells. It does this by depleting glutathione (GSH), a key antioxidant in the body. This leads to a rise in reactive oxygen species (ROS), which disrupts the cells' ability to produce IL-17. But it’s not just a chemical sledgehammer—DMF also rewires the cells’ gene expression.

Key pathways involved include:
PI3K-AKT-FOXO1-T-BET signaling: This cascade shifts the identity of Tc17 cells, reducing expression of RORγt, a gene critical for IL-17 production, and increasing T-BET, associated with cytotoxic T cells.

STAT5 signaling: Activated by IL-2, this pathway further suppresses IL-17 in a ROS-dependent way.

Epigenetic changes: DMF alters histone modifications at the IL-17 gene locus, reducing accessibility and shutting down expression. Together, these changes convert Tc17 cells into less inflammatory, more cytotoxic-like cells—a beneficial transformation in the context of MS.

Mouse Models Confirm the Findings
The team also tested DMF in mice with experimental autoimmune encephalomyelitis (EAE), a widely used model for MS. Both therapeutic and preventive DMF treatment led to:

Lower disease severity

Fewer Tc17 cells in the brain and spinal cord

Reduced IL-17 expression

A decline in overall immune cell infiltration into the CNS

Moreover, when Tc17 cells were treated with DMF before being transferred into disease-resistant mice, they failed to “help” CD4+ T cells trigger MS-like disease—confirming the loss of their inflammatory potential.

Why This Matters
These results offer a clear, targeted mechanism by which DMF helps MS patients: it suppresses Tc17 cells specifically, via oxidative stress and genetic reprogramming. This finding not only demystifies how DMF works but also opens new therapeutic avenues. Drugs that mimic this pathway—by targeting GSH levels or manipulating the AKT-T-BET or STAT5 signaling axis—could provide alternative or complementary options.

Even more importantly, the study suggests that Tc17 cell levels might predict who will benefit most from DMF, offering a path toward personalized treatment plans in MS.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Lückel, C., Picard, F., Raifer, H. et al. IL-17+ CD8+ T cell suppression by dimethyl fumarate associates with clinical response in multiple sclerosis. Nat Commun 10, 5722 (2019).