ILC Shape Shifters

How a groundbreaking study in Nature Immunology is giving new understanding to COPD and the role of innate lymphoid cells

The facts about chronic obstructive pulmonary disease (COPD) are devastating. From the American Lung Association, we know that it’s the third leading cause of death in the United States; more than 11 million people have been diagnosed, but up to 24 million may have it without even knowing it; there is no cure; and the number of people dying from COPD is growing.

As researchers, we feel the burden of those statistics—and our goal is to change them.

Revealing transformation

This month, we published data from our study on a novel role of innate lymphoid cells (ILCs) in COPD in Nature Immunology. The research opens up a new pathway in COPD that offers a significant step toward understanding the pathogenesis of the disease, and even other inflammatory conditions, and can help identify opportunities for therapeutic intervention.

It’s a confidence built on some quite striking revelations about how ILCs—a newly discovered group of innate immune cells that act as “one of the first responders” to infection—by literally transforming from one subset to another when exposed to triggers associated with COPD such as cigarette smoke or infection.

More specifically, we found that tissue-protective ILC2s change and acquire physical characteristics similar to inflammatory ILC1s in the presence of two inflammatory signals: Interleukin (IL)-12 and IL-18. This phenotypic switch has biological relevance, as increased ILC1 cells exacerbate the inflammatory response to infection.

We believe the same thing may be happening in patients with COPD. We find that patients with a higher ratio of circulating ILC1s in their blood have more severe disease and a prior history of frequent exacerbations.

This work was a follow-up study from which we had previously observed that smoking alters the immune system’s activity in the lungs and seems to skew the activity of ILC2s (Kearley et al, Immunity 2015). We don’t fully understand why this phenomenon is triggered, or how it is controlled. But, now we know that by simply converting from one ILC subset into another, the immune system in some situations can switch between tissue protection and inflammation.

New therapeutic targets

It’s a testament to how versatile and adaptive the immune system can be. Plus, these data suggest that changes in circulating ILC populations may predict patients at risk, and even make it possible to treat COPD by manipulating the switch of ILC1s back into ILC2s. Knowing more about ILC2s, specifically—their triggers, and how activity and plasticity are regulated—may help us to discover ways to restrain chronic inflammatory diseases like COPD that are excessive and damaging.

At the very least, this research—and our other related study also being published this month in Nature Immunology that examines the impact of the cytokine IL-1 on ILC2 function and its plasticity —supports further investigation of these rare ILCs as therapeutic targets.