How a Common MS Drug Silences a Rogue Immune Cell — and Why That Matters

Multiple sclerosis (MS) is a chronic autoimmune disease that tricks the immune system into attacking the brain and spinal cord. Despite a number of effective treatments, we still don’t fully understand how many of these therapies work — or why they fail in some patients.

One such treatment is dimethyl fumarate (DMF), a widely used oral drug for MS. It’s known for dampening the overactive immune response seen in MS, but its precise mechanism has remained elusive. A new study dives deep into this mystery and highlights a surprising villain — and a potential biomarker of treatment success.

Meet Tc17: The Quiet Troublemaker
Researchers have long known that T cells play a central role in MS, particularly the CD8+ subset, which are often more abundant than CD4+ cells in MS brain lesions. Among these, a lesser-known subtype called Tc17 cells (CD8+ T cells that produce the inflammatory molecule IL-17) stands out. These cells are potent amplifiers of inflammation in the brain and spinal cord, and their presence correlates with disease severity.

Surprisingly, Tc17 cells differ from the “killer” CD8+ T cells we usually hear about. They don’t destroy infected cells. Instead, they secrete IL-17 — a pro-inflammatory signal that worsens autoimmunity. These cells are also more dependent on specific biochemical pathways, which makes them a vulnerable target for intervention.

DMF Selectively Disarms Tc17 Cells
The breakthrough in this study? The researchers found that DMF therapy significantly reduces the number of Tc17 cells — but not Th17 (CD4+ IL-17-producing) cells — in people with MS who respond well to treatment. This effect was also observed in mice with an MS-like disease.

Even more intriguing, this suppression of Tc17 activity wasn’t just a side effect — it appeared to be a predictor of treatment success. Patients with higher Tc17 levels before starting DMF were more likely to respond well, and those levels dropped dramatically after treatment in responders.

How Does DMF Work Its Magic?
The study revealed a multi-step molecular cascade that DMF triggers in Tc17 cells:

Depleting Glutathione (GSH): DMF lowers levels of this antioxidant, leading to an increase in reactive oxygen species (ROS).

Boosting ROS: Elevated ROS levels, in turn, interfere with the cell’s ability to produce IL-17.

Activating PI3K-AKT-T-BET Pathway: This key signaling pathway downregulates the master IL-17 regulator (RORγt) and promotes a shift towards a more traditional “killer” T cell identity.

Involving STAT5 Signaling: DMF enhances IL-2-mediated STAT5 activity, which also inhibits IL-17 production.

Epigenetic Remodeling: DMF changes the accessibility of the IL-17 gene by altering histone marks — effectively silencing it at the DNA level.

The result? Tc17 cells become less inflammatory and lose their ability to “help” other harmful immune cells infiltrate the central nervous system.

Implications: A Path Toward Personalized MS Therapy
This research provides a powerful insight: Tc17 suppression could serve as a biomarker for DMF effectiveness. That means in the future, doctors might be able to test a patient’s Tc17 levels before prescribing DMF — improving outcomes and avoiding ineffective treatments.

It also opens the door to new therapies aimed directly at IL-17-producing CD8+ T cells, not just for MS but for other autoimmune diseases like psoriasis or rheumatoid arthritis where these cells play a role.

Final Thoughts
In the realm of autoimmunity, not all immune cells are created equal. By unraveling the nuanced effects of DMF on Tc17 cells, this study brings us a step closer to precision medicine in MS. It's a compelling example of how understanding the “how” behind a treatment can guide smarter, more personalized care.

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). https://doi.org/10.1038/s41467-019-13731-z