Scientists designed proteins to silence rogue immune cells

Researchers have designed a protein that can selectively shut down immune cells responsible for autoimmune diseases such as type 1 diabetes, multiple sclerosis, and hepatitis, but has not greatly weakened the body’s defense against infections and cancer.

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

The approach addresses the long-term challenge of treating autoimmune diseases in which T cells mistakenly attack the body’s own tissues rather than foreign invaders. Current treatments usually inhibit the entire immune system, causing dangerous vulnerability to infection and malignant tumors.

“Our findings reveal a complex mechanism that enables careful treatment of T-cell-driven autoimmune diseases that currently lack effective immunotherapy,” explained Jun Wang, assistant professor in the Department of Pathology at the NYU Grossman School of Medicine.

Approaching the solution

The team found that the spatial relationship between proteins on the surface of T cells is crucial to controlling immune responses. They found that when T cell receptors (TCRSs) approached a checkpoint protein called LAG-3, LAG-3 could effectively dial T cell activity by destroying the key activation signal.

In a healthy immune response, this proximity occurs naturally but is inconsistent. The researchers designed a “bispecific” antibody that forces these proteins to stay close, significantly enhancing LAG-3’s ability to inhibit hyperactive T cells.

Key details not highlighted in the press release: The team found that the proximity of LAG-3 allows it to physically interact with a portion of T cell receptors called CD3ε, enough to disrupt its ligation with LCK, an enzyme necessary for T cell activation.

Targeted treatment success

The engineered antibodies, known as LAG-3/TCR bispecific T cell muffler (BITS), have been proven to be effective in a variety of disease models:

• Reduced inflammatory damage to insulin-producing cells in type 1 diabetes model
• Reduced T cell infiltration and liver damage in autoimmune hepatitis
• When preventive, prevent symptoms of disease in multiple sclerosis models
• Two major types of T cells involved in autoimmune diseases (CD8+ and CD4+)

Strategic Advantages

Compared with other immune checkpoints, this method utilizes the unique features of LAG-3. While LAG-3 is not as effective as the PD-1 checkpoint used in cancer treatment, this limitation has become an advantage of autoimmune therapy. The spatial requirements of LAG-3 make it ideal for targeted inhibition without the need to turn off immune surveillance completely.

“We found that when the surface of the T cell is close to MHC-II, the T cell receptor is particularly close to LAG-3,” said Jasper DU, a medical student at Wang’s Lab. “This is the first time we have found that this proximity is at the heart of the ability of lag-3 to dial back T cell activity.”

From laboratory to potential treatment

The study is based on decades of antibody engineering, extending from single-target to dual-target therapeutic antibodies. By designing a molecule that can achieve protein proximity rather than simply blocking or activating individual targets, the team has opened up new avenues for precise immunotherapy.

The spatial approach can provide treatment for other diseases requiring precise immunomodulation. “Our research promotes our understanding of LAG-3 biology and may promote more approach-based, space-guided therapeutic designs, such as immunotherapy for other human diseases,” said co-optional author Jia You.

As more than 50 million Americans are affected by autoimmune diseases, targeted therapies that can inhibit the development of harmful immune responses without compromising protective immunity is a major advance. Researchers have set up a startup to commercialize its discoveries and show confidence in turning this lab discovery into clinical applications that could benefit patients facing these challenging diseases.

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