New understanding of immune modulator interleukin-2 guides drug discovery

March 17, 2020

The signaling molecule interleukin-2 (IL-2) has long been known to have powerful effects on the immune system, but efforts to harness it for therapeutic purposes have been hampered by serious side effects. Now researchers have worked out the details of IL-2's complex interactions with receptor molecules on immune cells, providing a blueprint for the development of more targeted therapies for treating cancer or autoimmune diseases.

IL-2 acts as a growth factor to stimulate the expansion of T cell populations during an immune response. Different types of T cells play different roles, and IL-2 can stimulate both effector T cells, which lead the immune system's attack on specific antigens, and regulatory T cells, which serve to rein in the immune system after the threat is gone.

"IL-2 can act as either a throttle or a brake on the immune response in different contexts," said Nikolaos Sgourakis, assistant professor of chemistry and biochemistry at UC Santa Cruz. "Our investigation used detailed biophysical methods to show how it does this."

Sgourakis is a corresponding author of the new study, published March 17 in Proceedings of the National Academy of Sciences. First author Viviane De Paula, a visiting scientist in his lab from the Federal University of Rio de Janeiro, used nuclear magnetic resonance spectroscopy (NMR) to observe IL-2's structural dynamics. The study was done in close collaboration with corresponding author Christopher Garcia's group at Stanford University.

The researchers were able to show that IL-2 adopts two different structural forms (termed conformations) that affect how it interacts with the receptors on different types of T cells. In solution, IL-2 naturally shifts back and forth between a minor conformation and a major conformation. The study also showed how certain mutations or interactions with other molecules can bias IL-2 toward adopting one conformation or the other.

"We have now come one step closer to a detailed understanding of how the IL-2 cytokine works," de Paula said. "It is the first time that anyone has managed to observe a transient state of IL-2 directly. With the use of NMR, we were able to describe the structure, dynamics, and function of IL-2 in its two conformations."

The study opens up numerous possibilities for designing drugs to stabilize IL-2 in a particular conformation for therapeutic applications.

"We can use this information to tweak the balance, depending on what we want to achieve in a clinical setting," Sgourakis said. "To target regulatory T cells, we would want to stabilize the minor conformation, and to target effector T cells, we would want to stabilize the major conformation."

Previous efforts by other researchers had already shown that different monoclonal antibodies targeting IL-2 could promote the expansion of different T cell populations in mice. One of these antibodies in complex with IL-2 was effective in treating mouse models of autoimmune disease and inflammation. And a similar human monoclonal antibody is currently heading toward clinical trials for the treatment of autoimmune diseases.

The new study provides a mechanistic explanation for these effects that can guide further drug discovery efforts.

"The details of the mechanism we present offer a direct blueprint for drug discovery," said Garcia. "Every drug company wants to know how to engineer this cytokine, and this paper provides some of the first really bona fide structural clarity on the fascinating topic of IL-2 dynamics."
-end-
In addition to De Paula, Garcia, and Sgourakis, the coauthors include Kevin Jude and Caleb Glassman at Stanford and Santrupti Nerli at UC Santa Cruz. This work was funded by the National Institutes of Health.

University of California - Santa Cruz

Related Immune System Articles from Brightsurf:

How the immune system remembers viruses
For a person to acquire immunity to a disease, T cells must develop into memory cells after contact with the pathogen.

How does the immune system develop in the first days of life?
Researchers highlight the anti-inflammatory response taking place after birth and designed to shield the newborn from infection.

Memory training for the immune system
The immune system will memorize the pathogen after an infection and can therefore react promptly after reinfection with the same pathogen.

Immune system may have another job -- combatting depression
An inflammatory autoimmune response within the central nervous system similar to one linked to neurodegenerative diseases such as multiple sclerosis (MS) has also been found in the spinal fluid of healthy people, according to a new Yale-led study comparing immune system cells in the spinal fluid of MS patients and healthy subjects.

COVID-19: Immune system derails
Contrary to what has been generally assumed so far, a severe course of COVID-19 does not solely result in a strong immune reaction - rather, the immune response is caught in a continuous loop of activation and inhibition.

Immune cell steroids help tumours suppress the immune system, offering new drug targets
Tumours found to evade the immune system by telling immune cells to produce immunosuppressive steroids.

Immune system -- Knocked off balance
Instead of protecting us, the immune system can sometimes go awry, as in the case of autoimmune diseases and allergies.

Too much salt weakens the immune system
A high-salt diet is not only bad for one's blood pressure, but also for the immune system.

Parkinson's and the immune system
Mutations in the Parkin gene are a common cause of hereditary forms of Parkinson's disease.

How an immune system regulator shifts the balance of immune cells
Researchers have provided new insight on the role of cyclic AMP (cAMP) in regulating the immune response.

Read More: Immune System News and Immune System Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.