Burst of accumulated zinc shows how the mineral boosts immune function, suggesting ways to improve health

Using mice, the team discovered that zinc is needed for the development of disease-fighting immune cells called T cells and prompts regeneration of the thymus, the immune organ that produces T cells.

"This study adds to our knowledge of what zinc is actually doing in the immune system and suggests a new therapeutic strategy for improving recovery of the immune system," said senior author Dr. Jarrod Dudakov, an immunologist at Fred Hutch.

The study also revealed that an experimental compound that mimics zinc's action in this organ works even better than the natural mineral to promote immune recovery.

"We are now looking into how zinc may fit in with our other discoveries of how the immune system repairs itself and could eventually lead to therapies to improve immune function for people who receive a blood stem cell transplant for a blood cancer or people with chronic immune decline that accompanies aging," Dudakov said.

Thymic regeneration and immune function, and zinc

Previously, Dudakov and his team have outlined the molecular pathways and cell types that govern how the immune system's thymus repairs itself after injury. Such treatments could improve vaccine efficacy and hasten thymic regeneration after stressors like chemotherapy, blood stem cell transplant and radiation exposure.

Dudakov began studying zinc a few years ago when Dr. Lorenzo Iovino, the study's first author and a research associate at Fred Hutch, joined Dudakov's lab. Since the scientists knew that low levels of zinc are linked to fewer infection fighting T cells and a shrunken thymus, where T cells develop, Dudakov and Iovino explored how to supplement with zinc in mouse models where the immune system is damaged.

Iovino, who's also a blood stem cell transplant physician, had shown in a previous study that zinc could boost immune recovery in patients undergoing stem-cell transplants for the blood cancer multiple myeloma.

But the study didn't explain why zinc was helping.

Zinc is critical for T-cell development and thymic regeneration

As in humans, Iovino and Dudakov found that the thymuses of mice deprived of dietary zinc shrink and produce notably fewer mature T cells, even after as little as three weeks of a no-zinc diet. Iovino was able to show that without zinc, T cells cannot fully mature.

He also found that zinc deficiency slows recovery of T-cell numbers after mice receive immune-destroying treatments akin to those given to patients about to receive a blood stem cell transplant.

Conversely, extra zinc speeds this process, and T cells recover faster than normal. The team saw a similar result in a mouse model of blood stem cell transplant.

"So we had a consistent result of a better reconstitution of the thymus and also a better reconstitution of T cells in the peripheral blood after zinc supplementation," Iovino said. "But we still didn't know how exactly zinc was working."

Iovino discovered that it was the change in zinc levels around cells that release a key regenerative factor that seemed to kick off the thymus' renewal processes. T cells accumulate zinc as they develop, but release it after a damaging event -- like a burst of radiation -- kills them off.

Cells use a molecule called GPR39 to sense a change in external zinc, and Iovino found that an experimental compound that mimics rising external zinc levels by stimulating GPR39 could also promote renewal factor release and thymic regeneration.

"What we think is going on is, as you give zinc supplementation, that gets accumulated within the developing T cells. It gets stored and stored and stored, then the damage comes along and the zinc is released," Dudakov said. "Now you have more zinc than you normally would, and it can instigate this regenerative pathway. With the experimental compound we can just directly target GPR39 and basically get the same effect without any of that pretreatment."

Getting to the clinic

There's still a lot to learn before they can turn their findings to therapeutic strategies, the scientists said.

Transplant patients already receive mineral supplements, so if extra zinc were to be incorporated into their treatment regimens, it would be important to make sure that anyone receiving it is truly zinc-deficient. Iovino thinks many patients might be, but right now there isn't a good test to assess this. He's currently working on developing one, which would first be used to help researchers determine whether patients' zinc status correlates with immune recovery after blood stem cell transplant.

Dudakov will pursue GPR39-stimulating compounds as therapies to improve thymic recovery after acute injuries like pre-transplant radiation. The team is currently screening similar compounds to find any that may be more effective.

He and Iovino are also working to determine whether such compounds could help with thymic regeneration in other settings. Unfortunately, our thymuses also slowly shrink and reduce their T-cell output as we age. Dudakov and Iovino would also like to know whether this chronic degeneration could be slowed by boosting the organ's regenerative processes.

"Our lab is continuing to piece together the molecular players that contribute to thymus regrowth," Dudakov said. "Ultimately, we aim to develop therapies that trigger natural regeneration and restore immune health."

The study was funded by the National Institutes of Health, the American Society of Hematology and The Rotary Foundation.