From burnout to endurance: Coaching immune cells to go the distance

Whether it’s flu, food poisoning or more severe challenges like cancer, our immune system works tirelessly to protect us.

In particular, white blood cells known as T cells play a pivotal role in tackling long-term, chronic illnesses.

But what happens when T cells run out of steam, like marathon runners pushed beyond their limits? They become exhausted. In this state, they lose their ability to perform at their peak, allowing disease to progress.

This phenomenon, known as T cell exhaustion, is a common feature found in response to health conditions like cancer and chronic infections and remains a major obstacle in advancing effective treatments against such long-term diseases.

Imagine an immune response that does not burn out after the first lap but can sustain its performance across the entire course.

Addressing T cell exhaustion has been a key focus in immunology, with researchers acutely aware that finding a way to keep immune cells performing at their best could unlock new frontiers in the treatment of chronic disease and cancer.

Health & Medicine

How severe viral infections overwhelm immune cells

Training the immune system against long-lasting threats

After years of investigating the mechanisms that govern immune responses, our research team has discovered a specialised type of immune cells, called ‘stem-like T cells’, that can keep the immune system in the game for the long haul.

This finding could be a game-changer for therapies targeting chronic diseases and cancer.

When dealing with acute infections, immune cells often behave like sprinters, mobilising quickly to eliminate the threat. Chronic conditions, however, require a different approach, one that balances persistence with efficiency, like in a marathon.

In our study, published in Science Immunology, we found that stem-like T cells are like elite athletes: uniquely equipped to adapt to the demands of both short- and long-term immune responses, unravelling the crucial role they play in the immune system.

They serve as a reserve pool, replenishing the body’s supply of active immune cells to sustain the immune response over time.

By tracking their development, we discovered that stem-like T cells rely on a protein called ID3, expressed by the gene of the same name, to unlock their potential and assign them their role in both acute and chronic infections.

Acting like a coach, ID3 instructs the cells to conserve energy while preparing them for their next big challenge. Importantly, we found that ID3 is instrumental in maintaining long-lasting T cell responses.

Health & Medicine

Deciphering ‘cell talk’ to understand our evolution

Our research also showed for the first time that stem-like T cells share a common origin with memory T cells, which remember past infections and mount rapid responses to recurring threats.

This challenges previous assumptions and provides new insights into the immune system’s adaptability.

By tracing their shared ancestry, we can better understand how the immune system balances immediate responses with long-term protection.

Stronger and more sustained response against disease

The discovery of stem-like T cells and their regulation by ID3 marks a major step forward in understanding the immune system’s complexity.

We also found that certain signals in the body could increase the number of ID3+ T cells, opening exciting possibilities for improving immunotherapy and enhancing the quality of life for patients battling chronic infections and cancer.

Cutting-edge treatments like CAR T cell therapy and adoptive T cell therapy rely on engineering a patient’s immune cells to recognise and attack cancer.

While these therapies have shown great promise, their effectiveness can decline over time due to T cell exhaustion.

Health & Medicine

Closing the NET on rare cancers

Like athletes who receive tailored training to perform at their peak, targeting the signals that activate ID3 can 'train' stem-like T cells to become elite athletes, functioning more effectively in chronic disease settings, bypassing T cell exhaustion.

By identifying what can boost the production of these supercharged T cells – capable of resisting burnout and maintaining a powerful immune response over time – our findings could pave the way for advancements in immunotherapy treatments like CAR T cell therapy.

This approach could also extend to vaccine development. Vaccines designed to stimulate the production of stem-like T cells could provide longer-lasting protection.

Overall, these results are deeply rewarding, reflecting years of collaboration, observation and an unwavering drive to better understand the immune system.

It’s a reminder that, much like training for a race, scientific discovery demands persistence, teamwork and a clear goal.

While more work is needed to translate these findings into real-world applications, harnessing the unique strengths of stem-like T cells and their regulation paves the way for innovative treatments that could redefine how we tackle chronic diseases and cancer.

This study is a collaborative effort between the Doherty Institute, the Peter MacCallum Cancer Centre, La Trobe University, Northwestern University (USA), the Olivia Newton-John Cancer Research Institute, the University of Birmingham (UK) and the University of Melbourne.