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. 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. From a clinical perspective, both IL-2 agonism and antagonism are of considerable importance, and it has been used for more than three decades toward immunotherapies of malignancies. The unique conformational plasticity of IL-2 appears to play an important role in targeting the IL-2 receptor signaling axis in both agonist and antagonist mode. However, this plasticity also presents an opportunity to target or otherwise manipulate the conformational landscape of IL-2 for drug discovery. 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.

A team from the University of California in Santa Cruz, led by Dr. Viviane De Paula, 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. The study opens up numerous possibilities for designing drugs to stabilize IL-2 in a particular conformation for therapeutic applications. 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. Nikolaos Sgourakis, assistant professor of Chemistry and Biochemistry at UC Santa Cruz, explained: “IL-2 can act as either a throttle or a brake on the immune response in different contexts. Our investigation used detailed biophysical methods to show how it does this. We have now come one step closer to a detailed understanding of how the IL-2 cytokine works. 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. We can use this information to tweak the balance, depending on what we want to achieve in a clinical setting. 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. The details of the mechanism we present offer a direct blueprint for drug discovery. 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”.

The new study has been published this week in the journal Proceedings of the National Academy of Sciences.

• Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

De Paula VS et al., Sgourakis NG. PNAS USA. 2020 Mar 17. 

McShan AC et al. PNAS USA 2019 Dec; 116(51):25602-613.

Natarajan K et al. Front Immunol. 2018 Jul 17; 9:1657.