In research that flips the investigative script by focusing on homeostasis rather than disease states, the Lynch Lab has discovered that certain innate T cells in the immune system rely on the molecular clock to maintain homeostasis in adipose, or fat, tissue.

These ‘gamma delta’ T cells respond to circadian rhythms to produce the cytokine called IL-17 which in turn engage or disengage a process called de novo lipogenesis. This essential process converts sugar from food and stores it as fat, for future use, allowing the body to maintain its core temperature during the cold, for example, or deploy fuel as energy.

The lab used single-cell RNA sequencing, a molecular-clock reporter, and genetic manipulations to show that innate IL-17-producing T cells are enriched for molecular-clock genes as compared with other T cells that don’t produce IL-17; when the clock genes were knocked out, IL-17 was no longer produced in a daily rhythm.

Their research also underscores a delicate balance in the whole-body metabolic rhythm that is grounded in this process. If the adipose tissue is not producing IL-17 because, for instance, sleep/wake cycles are disturbed, then de novo lipogenesis is not properly engaged, and the body’s energy stores suffer. But if it is overproducing IL-17, the consequences can include illnesses like fatty liver disease or diabetes.

And all of this complex interdependency—between the metabolic and immune systems, the production of IL-17 by gamma delta T cells, and de novo lipogenesis—is overseen by the mammalian molecular clock.

The lab’s research, Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis, was reported in Nature last month by a team of collaborators under Lydia Lynch, member of the Ludwig Princeton Branch and professor in the Department of Molecular Biology.

Researchers have recently begun to probe more deeply the workings of the molecular clock, starting with the award of the 2017 Nobel Prize in Chemistry to the three men who discovered it by isolating a gene that controls the daily biological rhythm.

Lynch’s research expands on our understanding of this rhythm—and indeed, whole-body metabolism—by showing communication between the immune and metabolic systems to maintain homeostasis, and proving its connection to IL-17.

“It is commonly thought that the immune system is just sitting around and waiting for a pathogen to come along to activate it. But it’s not."

"It’s doing something all the time. It has a maintenance role, too, that is important for our whole body to run properly. And it’s important to study how the immune system does this maintenance role as well as its role of defense,” said Lynch.

“We now know that there’s an immune system in fat. In the beginning, this was confusing because you don’t really get infections or cancer in your fat. So what do you need to have the immune system there for? And we found that gamma delta T cells live in fat and are making this IL-17. Every night (for a nocturnal mouse), it’s doing this important job. All cells have this molecular clock, but cells that make IL-17 express more clock genes and are much more strongly regulated by the clock.

“If you have no IL-17 or if you remove the molecular clock genes, you can’t do de novo lipogenesis. So, the immune system is playing a role in adipose tissue’s ability to maintain whole-body homeostasis.”

The Lynch Lab focuses on whole-body metabolism and its impact on the immune system and cancer. But the lab also turns that mission around, investigating how the immune system influences whole-body metabolism. For the Ludwig Princeton Branch specifically, Lynch’s research tackles the question of how obesity and diet affect the immune system’s ability to kill cancer.

“One of the big questions we want to ask here at Ludwig is, can diet really change the course of cancer?” said Lynch.

“And we really want to understand at the biochemical and molecular level how diet affects the immune system’s ability to detect and kill cancer. We really don’t know the mechanisms, and so we’re trying to take a holistic approach.”

This research, she said, is an outgrowth of that approach.

Lynch emphasizes that while the research highlights results with mice, she believes that IL-17 is also “on the clock” in humans. Using publicly available data in which people have been treated with anti-IL-17 biologics, researchers found that de novo lipogenesis in skin was also down-regulated after blocking IL-17.

“We’re going to do a couple of things next through Ludwig,” said Lynch. “IL-17 is a pro-tumor cytokine, for instance. So we’re wondering if IL-17 is also boosting fat metabolism in tumor cells the way it is in the liver and adipose tissue. We’ll test that next. We’re looking forward to more work in this area.”