Prolonged illnesses like cancer and chronic infections often lead to a devastating phenomenon: immune exhaustion. The body’s immune system, particularly the T cells that are its frontline defenders, becomes unable to function effectively over time, making it harder to fight off persistent threats. This challenge has long stood in the way of effective treatments for diseases like cancer, HIV, and hepatitis, where the immune system’s ability to sustain a potent response weakens over time. However, recent research led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute) and the Peter MacCallum Cancer Center (Peter Mac) has uncovered an exciting new avenue for tackling immune exhaustion.
In a groundbreaking study published in Science Immunology, scientists identified a rare group of immune cells called stem-like T cells, which possess an extraordinary ability to self-renew and resist exhaustion. These T cells, known as ID3+ T cells, could provide the key to maintaining powerful, long-term immune responses in the fight against chronic infections and cancer.
The Discovery of ID3+ T Cells
The study’s findings reveal that the unique endurance of these stem-like T cells is driven by a protein called ID3, which is encoded by the ID3 gene. ID3+ T cells are different from other T cells because they can continuously renew themselves and remain functional even after long-term exposure to chronic diseases. This gives them the ability to sustain strong immune responses, unlike conventional T cells, which typically become exhausted and ineffective in the face of prolonged infection or cancer.
Catarina Gago da Graça, a Ph.D. candidate at the Doherty Institute and co-first author of the study, emphasized the significance of these findings, saying, “ID3+ T cells have the remarkable ability to resist burnout and maintain a powerful immune response over time, making them particularly effective in the face of chronic infections or cancer.” This ability to avoid exhaustion makes ID3+ T cells an exciting area of research for improving treatments for diseases that have long eluded effective therapy.
The Role of ID3 in Immune Endurance
The critical factor driving the endurance of these stem-like T cells is the protein ID3. By expressing ID3, these cells are able to resist the usual decline in immune function that other T cells experience when they are exposed to persistent threats. For patients suffering from chronic diseases, this discovery is a potential game-changer. The ability of ID3+ T cells to self-renew allows them to keep fighting off infections or cancer long after other immune cells would have become ineffective.
Professor Ricky Johnstone, Executive Director of Cancer Research at Peter Mac and co-lead author of the study, explained how ID3+ T cells could improve immunotherapies, saying, “We discovered that ID3+ T cell formation could be promoted by specific inflammatory cues, potentially offering new strategies to boost the number of immune cells that excel at fighting cancer in patients.”
Improving Treatments for Cancer and Chronic Infections
One of the most exciting implications of this discovery is its potential to improve immunotherapy treatments, particularly CAR T cell therapy. While CAR T cell therapy has already shown transformative results for some cancer patients, its effectiveness can diminish over time due to T cell exhaustion. By enhancing the activity of ID3+ T cells, researchers believe they can create more resilient T cells that have the endurance to combat cancer more effectively and for a longer duration.
Professor Johnstone also highlighted the broader implications for cancer treatment, saying that this research could lead to therapies that are more potent and long-lasting. “This could lead to better treatments for cancer patients and improve clinical immunotherapy outcomes,” he added.
Moreover, the study’s findings extend beyond cancer therapy. Chronic infections like HIV, hepatitis B, and hepatitis C also involve immune exhaustion, making them difficult to treat. By promoting the formation of ID3+ T cells, doctors could potentially reinforce the immune response in these patients, providing a stronger, more sustained defense against the infections.
A Collaborative Effort to Combat Immune Exhaustion
The research represents the collaborative work of multiple institutions, including the Peter Doherty Institute, Peter MacCallum Cancer Center, La Trobe University, Northwestern University (U.S.), the Olivia Newton-John Cancer Research Institute, the University of Birmingham (UK), and the University of Melbourne. This global effort has shed light on the immune system’s secret weapon—stem-like T cells—and how they can help overcome one of the biggest challenges in treating chronic diseases.
Dr. Daniel Utzschneider, a Laboratory Head at the Doherty Institute, explained how this research could pave the way for new, more effective treatments: “Exhausted immune cells remain one of the biggest challenges in treating chronic diseases. This research provides a roadmap for how we might reinvigorate the immune system to improve health outcomes for people living with cancer or chronic infections like HIV or hepatitis B and C, thanks to these stem-like T cells, the immune system’s secret power.”
Potential for Advancements in Vaccines and Immunotherapies
In addition to improving cancer treatments, this discovery has the potential to influence the development of vaccines that provide long-lasting protection against chronic diseases. By incorporating strategies that boost the activity of ID3+ T cells, researchers could help the immune system mount a more durable defense against infections, making vaccines even more effective in preventing diseases like HIV or hepatitis.
The study’s authors believe that by harnessing the power of ID3+ T cells, the field of immunotherapy could experience a significant breakthrough. Whether in the form of enhanced CAR T cell therapies, new cancer treatments, or more effective vaccines, the potential to revitalize the immune system offers hope for millions of people battling chronic diseases.
A Roadmap for Future Research
While the findings are promising, there is still much to learn about the mechanisms that regulate the formation and function of ID3+ T cells. As researchers continue to study these cells, they will work to identify the specific signals and pathways that trigger the formation of these immune cells. The goal is to find ways to harness these signals therapeutically, boosting the body’s natural ability to fight off chronic diseases and preventing immune exhaustion from derailing treatment efforts.
Conclusion
The discovery of ID3+ T cells marks an exciting turning point in immunology. These stem-like cells have the potential to transform the treatment of chronic infections and cancer by offering a way to overcome the problem of immune exhaustion. By self-renewing and resisting burnout, these cells could provide a more enduring and powerful defense against persistent diseases, opening up new possibilities for immunotherapies and vaccines that offer long-lasting protection.
As research continues to advance, the hope is that strategies to enhance ID3+ T cells will become a cornerstone of cancer immunotherapy and other chronic disease treatments. The work done by the Doherty Institute, Peter Mac, and their collaborators is a step toward better therapies, more effective vaccines, and a future where the immune system is better equipped to fight off even the most persistent diseases.
Reference: Catarina Gago da Graça et al, Stem-like memory and precursors of exhausted T cells share a common progenitor defined by ID3 expression, Science Immunology (2025). DOI: 10.1126/sciimmunol.adn1945