IRF-5 identified as key to preventing immune cell exhaustion

In fighting chronic infections or certain cancers, CD8+ T cells-the immune system's frontline soldiers-eventually become exhausted. They lose effectiveness and respond less efficiently to threats. This weakening is a major therapeutic challenge, as it limits the body's ability to fight chronic infections.

However, the team of Professor Simona Stäger at Institut national de la recherche scientifique (INRS), in collaboration with colleagues from INRS and McGill University, has identified a key game changer: IRF-5. This transcription factor appears to preserve the energy and vitality of CD8+ T cells by acting directly on their metabolism.

These findings, recently published in The EMBO Journal, highlight the importance of fundamental research in understanding the immune system and developing innovative therapeutic approaches.

A key ally against T cell exhaustion

T cell exhaustion is caused by several factors, including an imbalance in internal cell functioning. Normally, T cells shift their energy production to respond quickly to infection. But when they are stimulated for too long-as during chronic infections-their metabolism becomes depleted. They produce fewer cytokines (chemical messengers essential to the immune response), their mitochondria (the cell's energy centres) function less efficiently, and they ultimately lose their effectiveness.

In this study, the team used the LCMV Clone 13 virus, a model of chronic infection, to explore the role of IRF-5 in CD8+ T cells. While the role of IRF-5 in other cell types is well known, its function in these immune cells had not been explored until now.

Our results show that IRF-5 acts as a guardian of T cell metabolism and mitochondrial function. It helps T cells maintain their energy and ability to fight, even under prolonged stress."

Simona Stäger, INRS professor and senior author of the study, expert in immunology of infectious diseases, and Vice-director of Infectiopole

The researchers found that the absence of IRF-5 worsens exhaustion. CD8+ T cells lacking IRF-5 showed disrupted lipid metabolism, increased mitochondrial oxidative stress, and reduced oxidative phosphorylation-all factors that impair their function.

A promising step toward better understanding immunity

This discovery opens the door to new strategies for boosting immunity to chronic infections or cancers, where T cell exhaustion is also observed.

"I hope our work will help us better understand how to modulate cellular metabolism to support and enhance immune responses during chronic infections or cancer. IRF-5 transcription factor could play a key role in this approach."

-Linh Thuy Mai, lead author of the study, former PhD student in virology and immunology from INRS, currently a postdoctoral fellow at Albert Einstein College of Medicine, United States.

Professor Stäger's laboratory is based at the INRS Armand-Frappier Santé Biotechnologie Research Centre, the sole North American member of the Pasteur Network .