How the Spleen Helps the Immune System Accept an Organ Transplant

New research from the University of Minnesota Medical School is offering a fresh and surprisingly optimistic way to think about how the immune system responds to organ transplants. Instead of viewing immune resistance as something that must always be shut down with lifelong drugs, this study shows that the body may already have a built-in system for learning tolerance — and the spleen sits right at the center of it.

The findings, published in Science Advances in January 2026, reveal that a process long considered harmful — T cell exhaustion — can actually play a protective and beneficial role in transplant acceptance. Even more importantly, the research explains how this process can be precisely controlled so that only transplant-specific immune responses are affected, while the rest of the immune system remains fully functional.

A New Perspective on Immune Tolerance in Transplants

For decades, transplant medicine has relied on broad immunosuppression. Patients who receive organs often need to take drugs for life that weaken their entire immune system to prevent rejection. While effective, these medications come with serious downsides, including increased infection risk, cancer susceptibility, kidney damage, and metabolic complications.

This new study challenges the idea that immune suppression is the only option. Instead, it focuses on immune education — teaching the immune system to recognize a transplanted organ as something that does not need to be attacked.

At the heart of this discovery is the spleen, an organ traditionally associated with blood filtration and immune surveillance, but now shown to function as a training hub for immune tolerance.

Why the Spleen Matters More Than We Thought

The researchers identified the spleen as a key control center where immune tolerance to a donor organ can be established. When properly guided, the spleen orchestrates a series of immune events that reduce the likelihood of transplant rejection without shutting down immune defenses across the body.

This finding is especially important because it explains where tolerance is generated and how it is maintained over time — two questions that have long puzzled transplant researchers.

Apoptotic Donor Leukocytes and Immune Reprogramming

A critical part of the study involved administering apoptotic donor leukocytes (ADLs). These are donor immune cells that have been programmed to undergo controlled cell death. When introduced into the recipient’s body, these cells do not provoke an aggressive immune response. Instead, they act as a signal.

The spleen recognizes these apoptotic cells and responds by expanding a specific group of immune regulators known as donor-specific Tr1 cells.

What Are Tr1 Cells and Why They Matter

Tr1 cells, or Type 1 regulatory T cells, are a specialized subset of T cells that help regulate immune responses. Unlike conventional regulatory T cells, Tr1 cells are particularly effective at producing anti-inflammatory signals and promoting immune calm without completely shutting down immune activity.

In this study, the Tr1 cells that emerged were allospecific, meaning they were trained to recognize only the donor tissue. This specificity is crucial. It allows the immune system to remain alert and capable of fighting infections, while selectively dampening the response that would otherwise attack the transplanted organ.

Turning T Cell Exhaustion Into an Advantage

One of the most striking findings of the research is the role of T cell exhaustion. Traditionally, T cell exhaustion has been associated with chronic infections and cancer, where overworked T cells lose their ability to function effectively. In most contexts, this is considered a failure of the immune system.

Here, however, exhaustion works differently.

The Tr1 cells generated in the spleen actively induce exhaustion in effector T cells that are most likely to cause transplant rejection. These effector T cells become less aggressive, less inflammatory, and less capable of damaging the donor organ.

Rather than being a random or harmful process, exhaustion becomes controlled, targeted, and beneficial.

The Areg–EGFR Signaling Pathway Explained

At the molecular level, this immune regulation depends on the Areg–EGFR signaling pathway.

Tr1 cells produce a molecule called amphiregulin (Areg), which interacts with the epidermal growth factor receptor (EGFR) on effector T cells. This interaction triggers changes inside those effector cells that push them into a state of exhaustion.

This pathway allows immune tolerance to develop without global immune suppression, making it one of the most promising aspects of the discovery. The immune system is not silenced — it is retrained.

Why This Matters for Transplant Patients

The implications for transplant medicine are significant. Long-term immunosuppression has always been a trade-off: preventing rejection at the cost of overall immune health. This research suggests that it may be possible to reduce or even eliminate the need for prolonged immunosuppressive therapy in some patients.

By inducing a donor-specific tolerant state, patients could maintain normal immune defenses against infections and cancers while still achieving long-term graft acceptance.

This is especially relevant for islet transplantation in patients with diabetes, where the burden of lifelong immunosuppression has limited broader adoption of the therapy.

Operational Tolerance and the Future of Transplantation

The study also sheds light on a concept known as operational tolerance — a state in which transplant recipients maintain a functioning graft without ongoing immunosuppressive drugs. While rare, operational tolerance has been observed in some patients, but the underlying mechanisms were poorly understood.

This research provides concrete biological evidence explaining how such tolerance might develop, and how it could be intentionally induced.

Beyond Transplants: Broader Implications for Immune Diseases

While the study focuses on organ transplantation, the findings may have broader applications. Selective immune regulation, rather than blanket suppression, could be useful in treating autoimmune diseases, chronic inflammatory conditions, and other immune-mediated disorders.

By leveraging spleen-centered immune programming, future therapies could aim to calm specific harmful immune responses while leaving protective immunity intact.

A Shift in How We Think About the Immune System

Perhaps the most important takeaway from this research is conceptual. It reframes the immune system not just as a force that must be restrained, but as a system that can be educated, guided, and fine-tuned.

The spleen, once seen as a supporting player, now emerges as a central architect of immune tolerance. And T cell exhaustion, once viewed only as a problem, becomes a powerful tool when used correctly.

Research Reference:
https://www.science.org/doi/10.1126/sciadv.aea0567