Scientists Design Protein That Silences Rogue Immune Cells

Researchers have engineered a protein that can selectively shut down the immune cells responsible for autoimmune diseases like Type 1 diabetes, multiple sclerosis, and hepatitis—without broadly weakening the body’s defenses against infections and cancer.

The study, published in Cell, demonstrates how holding two specific protein complexes together on T cells can eliminate autoimmune tissue damage while preserving normal immune function.

The approach addresses a longstanding challenge in treating autoimmune diseases, where T cells mistakenly attack the body’s own tissues instead of foreign invaders. Current treatments often suppress the entire immune system, creating dangerous vulnerabilities to infections and malignancies.

“Our findings reveal an intricate mechanism that enables a careful treatment approach to T-cell driven autoimmune diseases, which currently lack effective immunotherapies,” explains Jun Wang, assistant professor in the Department of Pathology at NYU Grossman School of Medicine.

The Proximity Solution

The research team discovered that spatial relationships between proteins on T cell surfaces are crucial for controlling immune responses. They found that when T cell receptors (TCRs) come close to a checkpoint protein called LAG-3, the LAG-3 can effectively dial down T cell activity by disrupting key activation signals.

In healthy immune responses, this proximity occurs naturally but inconsistently. The researchers engineered a “bispecific” antibody that forces these proteins to stay close together, dramatically enhancing LAG-3’s ability to suppress overactive T cells.

A critical detail not emphasized in the press release: The team discovered that LAG-3’s proximity allows it to physically interact with part of the T cell receptor called CD3ε, pulling on it enough to disrupt its connection with Lck—an enzyme essential for T cell activation.

Targeted Treatment Success

The engineered antibody, called LAG-3/TCR Bispecific T cell Silencer (BiTS), proved effective across multiple disease models:

• Reduced inflammatory damage to insulin-producing cells in Type 1 diabetes models
• Decreased T cell infiltration and liver damage in autoimmune hepatitis
• Prevented disease symptoms in multiple sclerosis models when given preventively
• Worked against both major types of T cells (CD8+ and CD4+) involved in autoimmune diseases

A Strategic Advantage

The approach leverages a unique feature of LAG-3 compared to other immune checkpoints. While LAG-3 is less potent than PD-1 checkpoints used in cancer therapy, this limitation becomes an advantage in autoimmune treatment. LAG-3’s spatial requirements make it ideal for targeted suppression without completely shutting down immune surveillance.

“We discovered that, as a T cell’s surface draws close to the MHC-II presenting its TCR trigger molecule, the T cell receptor gets particularly close to LAG-3,” noted co-first author Jasper Du, a medical student in Wang’s lab. “For the first time, we found that this proximity is central to the ability of LAG-3 to dial back T cell activity.”

From Lab to Potential Treatment

The research builds on decades of antibody engineering, extending from single-target to dual-target therapeutic antibodies. By designing a molecule that enforces protein proximity rather than simply blocking or activating individual targets, the team has opened a new avenue for precision immunotherapy.

The spatial approach could inform treatments for other diseases where precise immune modulation is needed. “Our study advances our understanding of LAG-3 biology and may foster more proximity-based, spatially-guided therapeutic designs like BiTS as immunotherapy for other human diseases,” remarked co-first author Jia You.

With over 50 million Americans affected by autoimmune diseases, the development of targeted therapies that can suppress harmful immune responses without compromising protective immunity represents a significant advance. The researchers have already formed a startup company to commercialize their findings, suggesting confidence in translating this laboratory discovery into clinical applications that could benefit patients facing these challenging conditions.