A new study published in the Journal of Immunology from scientists at Benaroya Research Institute (BRI) explores how the timing of a promising autoimmune therapy could shape immune responses to viral infections — sometimes with opposing effects. The study, led by Daniel Campbell, PhD, his graduate student Joe Albe, PhD, and other collaborators at BRI and Seattle Children’s Research Institute, demonstrates that a regulatory T cell (Treg)-selective interleukin-2 (IL-2) mutein can either dampen or intensify the immune response to influenza infection, depending on when it is administered.
Engineered IL-2 proteins known as “muteins” are designed to selectively stimulate Tregs — immune cells that suppress inflammation. They are being harnessed to treat autoimmune diseases such as type 1 diabetes and lupus. While these therapies aim to restore immune balance, they also carry the risk of broadly suppressing immunity, reducing vaccine efficacy, or even fueling excessive immune activation that leads to tissue damage.
To better understand these risks, BRI researchers used a murine model of influenza infection to test how this specific IL-2 mutein impacts the immune response. When administered before infection, it significantly expanded Tregs and suppressed flu-specific CD8⁺ T cells, key antiviral responders. This shift reduced flu-specific CD8⁺ T cell abundance and changed their location and characteristics in the lungs, without increasing viral burden or worsening illness.
However, when given during an active infection, this mutein had the opposite effect. It expanded flu-specific CD8⁺ T cells, boosted flu-specific responses, and worsened disease symptoms, despite not affecting virus levels. These results suggest that IL-2 muteins can directly stimulate activated T cells during infection, potentially exacerbating tissue damage caused by an overactive immune response.
