Signaling Modulator Interleukin-2 Guides Drug Discovery

New research has examined the details surrounding the signaling molecule interleukin-2 (IL-2) and its 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 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 researcher Nikolaos Sgourakis, assistant professor of chemistry and biochemistry at UC Santa Cruz, in a press release. "Our investigation used detailed biophysical methods to show how it does this."

In the study, published in Proceedings of the National Academy of Sciences, researchers used nuclear magnetic resonance spectroscopy (NMR) to observe the structural dynamics of IL-2. The researchers were then able to demonstrate that IL-2 adopts 2 different structural forms, or 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 demonstrated how certain mutations or interactions with other molecules can bias IL-2 toward adopting 1 conformation or the other.

According to the study authors, this is the first time that research has managed to observe a transient state of IL-2 directly. With the use of NMR, they were able to describe the structure, dynamics and function of IL-2 in its 2 conformations.

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

“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 research has shown that different monoclonal antibodies targeting IL-2 could promote the expansion of different T cell populations. One of these antibodies in complex with IL-2 was effective in treating models of autoimmune disease and inflammation. The new study provides a mechanistic explanation for these effects that can guide further drug discovery efforts, according to the authors.

Reference

• New understanding of immune modulator interleukin-2 guides drug discovery [news release]. Published March 17, 2020. https://news.ucsc.edu/2020/03/interleukin-2-dynamics.html. Accessed March 25, 2020.