Mass Migration of Immune Cells Found to Regulate Blood Glucose Levels

New research by scientists at the Champalimaud Foundation has revealed a surprising new role for the immune system. Their study in mice found that during periods of low energy— such as intermittent fasting—ILC2 immune cells step in to regulate blood sugar levels, acting as a “postman” in a previously unknown three-way conversation between the nervous, immune and endocrine systems. The findings could point to new strategies for managing disorders such as diabetes, obesity and cancer.

“For decades, immunology has been dominated by a focus on immunity and infection,” said Henrique Veiga-Fernandes, PhD, head of the Immunophysiology Lab at the Champalimaud Foundation. “But we’re starting to realize the immune system does a lot more than that.”

Veiga-Fernandes and colleagues reported on their findings in Science, in a paper titled “Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis.” In their report the team concluded that the collective data may grant “…increased knowledge on how neuronal and immune functions might be harnessed in the context of endocrine and metabolic disorders in humans.”

Glucose, a simple sugar, is the primary fuel for our brains and muscles. Maintaining stable blood sugar levels is crucial for our survival, especially during fasting or prolonged physical activity when energy demands are high and food intake is low.

Traditionally, blood sugar regulation has been attributed to the hormones insulin and glucagon, both produced by the pancreas. Insulin lowers blood glucose by promoting its uptake into cells, while glucagon raises it by signaling the liver to release glucose from stored sources. Glucagon is secreted to the blood by alpha cells located in the pancreatic islet of Langerhans, the authors explained. “Fasting or high energy–consumption sports activities can result in low plasma glucose concentrations and in response, glucagon secretion is stimulated to promote endogenous glucose production in the liver…while high plasma glucose concentrations trigger insulin secretion from pancreatic beta cells, low- plasma glucose drives glucagon secretion from alpha cells.

Veiga-Fernandes and colleagues suspected there was more to the story, however. “For example”, he noted, “some immune cells regulate how the body absorbs fat from food, and we’ve recently shown that brain-immune interactions help control fat metabolism and obesity. This got us thinking—could the nervous and immune systems collaborate to regulate other key processes, like blood sugar levels?” As the authors noted, referring to prior research, previous observations “…raised the hypothesis that the nervous and immune systems may cooperate to integrate body energy levels, thereby shaping endocrine function and establishing inter-organ communication routes that control glucose homeostasis.”

To explore this idea, the researchers conducted experiments in mice. They used genetically engineered mice lacking specific immune cells to observe their effects on blood sugar levels during fasting. They discovered that mice missing a type of immune cell called ILC2 couldn’t produce enough glucagon—the hormone that raises blood sugar—and their glucose levels dropped too low. “After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis,” they wrote. Veiga-Fernandes added, “When we transplanted ILC2s into these deficient mice, their blood sugar returned to normal, confirming the role of these immune cells in stabilizing glucose when energy is scarce.”

Realizing that the immune system could affect a hormone as vital as glucagon, the team knew they were onto something of major impact. But it left them asking: how exactly does this process work? The answer took them in a very unexpected direction.

“We thought this was all being regulated in the liver because that’s where glucagon exerts its function,” recalls Veiga-Fernandes. “But our data kept telling us that everything of importance was happening between the intestine and the pancreas.”

Using advanced cell-tagging methods, the team labeled ILC2 cells in the gut, giving them a glow-in-the-dark marker. After fasting, they found these cells had travelled to the pancreas. “Genetic photoconversion experiments revealed that fasting induced the migration of intestinal ILC2s to the pancreas, which was associated with the expression of genes associated with intestinal tissue residency being reduced in ILC2s,”  the investigators stated. Veiga-Fernandes continued, “One of the biggest surprises was finding that the immune system stimulates the production of the hormone glucagon by sending immune cells on a journey across different organs.”

The study showed that once in the pancreas, those immune cells release cytokines that instruct pancreatic cells to produce the hormone glucagon. The increase in glucagon then signals the liver to release glucose. “We found ILC2s within the islets of Langerhans and ILC2s or ILC2-derived cytokines triggered pancreatic alpha cells to secrete glucagon in vitro,” the authors explained. “When we blocked these cytokines, glucagon levels dropped, proving they are essential for maintaining blood sugar levels,” Veiga-Fernandes added.

“What’s remarkable here is that we’re seeing mass migration of immune cells between the intestine and pancreas, even in the absence of infection,” he noted. “This shows that immune cells aren’t just battle-hardened soldiers fighting off threats—they also act like emergency responders, stepping in to deliver critical energy supplies and maintain stability in times of need.”

The scientists found that this cell migration was orchestrated by the nervous system. During fasting, neurons in the gut connected to the brain release chemical signals that bind to immune cells, telling them to leave the intestine and go to a new “postcode” in the pancreas, within a few hours. The study showed that these nerve signals change the activity of immune cells, suppressing genes that anchor them in the intestine and enabling them to move to where they’re needed. They explained in their research article summary, “Our data provide evidence supporting that, during 16 hours of fasting, adrenergic neuronal signals reduced the expression of ILC2 gut-anchoring receptors and promoted ILC2 migration from the intestine to the pancreas, in which type 2 cytokines can stimulate the production of the hormone glucagon, triggering endogenous glucose production in the liver.”

Veiga-Fernandes noted. “This is the first evidence of a complex neuroimmune-hormonal circuit. It shows how the nervous, immune, and hormonal systems work together to enable one of the body’s most essential processes—producing glucose when energy is scarce.”

Mice share many fundamental biological systems with humans, suggesting this inter-organ dialogue also occurs in humans when fasting or exercising,” he continued. “By understanding the role of ILC2s and their regulation by the nervous system, we can better appreciate how these daily life activities support metabolic health. We’re eavesdropping on conversations between organs that we’ve never heard before.”

Veiga-Fernandes suggests that the immune system likely evolved as a safeguard during adversity, pointing out that our ancestors didn’t have the luxury of three meals a day and, if they were lucky, might have managed just one. This evolutionary pressure would have pressured our bodies to find ways to ensure that every cell gets the energy it needs.

“We’ve long known that the brain can directly signal the pancreas to release hormones quickly, but our work shows it can also indirectly boost glucagon production via immune cells, making the body better equipped to handle fasting and intense physical activity efficiently.”

In their report the team stated, “We provide evidence for an effector neuro-immune hub that responds to low energy levels, suggesting that brain areas that harbor glucose sensor circuits may regulate the small intestine, translating energy body states into peripheral immune functions that promote adequate endocrine responses…coupling direct and indirect adrenergic signals to induce fast and high glucagon levels and glucose mobilization may have ensured efficient life-saving responses to hypoglycemia, notably by ensuring brain function and muscle activity in the context of fight or flight responses.”

The findings could open new doors for managing a range of conditions, notably for cancer research. Pancreatic neuroendocrine tumors and liver cancer can hijack the body’s metabolic processes, using glucagon to increase glucose production and fuel their growth. In advanced liver cancer, this process can lead to cancer-related cachexia, a condition marked by severe weight and muscle loss. Understanding these mechanisms could help develop better treatments.

“Balancing blood sugar is also critical, not only for preventing obesity, but also for addressing the global diabetes epidemic, which affects hundreds of millions of people,” remarked Veiga-Fernandes. “Targeting these neuro-immune pathways could offer a new approach to prevention and treatment. This study reveals a level of communication between body systems that we’re only beginning to grasp,” he concluded. “We want to understand how this inter-organ communication works—or doesn’t—in people with cancer, chronic inflammation, high stress, or obesity. Ultimately, we aim to harness these results to improve therapies for hormonal and metabolic disorders.”