A research group at Karolinska Institutet in Sweden has analyzed tissues from human patients with inflammatory bowel disease (IBD) to find how certain immune cells known as innate lymphoid cells (ILCs) develop into mature cells that may play a role in the disorder. The study identified a marker that correlates to how human ILC precursors differentiate into various subsets, and showed that the marker’s absence helped to define a unique subgroup of ILCs in IBD patient samples. The findings could pave the way for more effective treatments against IBD, a disease that causes considerable suffering and that is linked to an increased risk of colorectal cancer.

“The function of ILCs changes during inflammation and therefore ILCs represent a promising therapeutic target for conditions like inflammatory bowel disease,” said Efthymia Kokkinou, PhD, a doctoral student at the department of medicine, Huddinge at Karolinska Institutet. “Insight into how these cells develop from immature cells into mature cells in tissue helps us understand how they influence tissue function or inflammation in mucosa and how they can be manipulated for therapeutic purposes.” Kokkinou is first author of the team’s report, which is published in Science Immunology, and titled, “CD45RA+CD62L ILCs in human tissues represent a quiescent local reservoir for the generation of differentiated ILCs,” in which the investigators concluded that their results “…have implications for understanding the functional diversification and plasticity of ILCs, especially in the context of IBD.”

IBD is characterized by chronic inflammation of the gut mucosa that is thought to increase the risk of colon cancer. The disease often starts before middle age, with symptoms that can include abdominal pain and weight loss. The cause is unknown but genetic, environmental, and immunologic factors are all believed to play a role. Many IBD patients don’t respond to available treatments, and scientists need to understand more about the mechanisms that drive the disease.

ILCs are lymphocytes, a family of immune cells, which are found in the mucosa where they form part of the immune system and maintain tissue function, such as the production of mucous. ILCs do for the innate immune system what T cells do for the adaptive immune system, and like there are for T cells, there are different types of ILC. “ILCs are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment,” the authors explained. “Human ILCs are classified in five categories that show a high degree of plasticity depending on the tissue microenvironment: natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer cells with specialized functions.”

Studying how ILCs transform into their subsets can reveal more about what innate immunity does during homeostasis and disease. Previous research has shown that ILCs change function during inflammation, making them a promising target for IBD treatment. To learn more about how ILCs differentiate, Kokkinou and colleagues isolated ILCs from the tonsils and gut tissue of patients who had undergone resection surgery or endoscopic examination. A total of 48 patients were involved in the study, 31 of whom had IBD. The ILCs were examined in detail, both immediately after isolation and after cell culture. Using flow cytometry and transcriptomics, the scientists discovered that the presence or absence of a marker called CD62L correlated with what type of ILC the precursor would become, offering a way to distinguish between two distinct subsets: CD62L+ and CD62L ILCs.

The team also found that only ILCs without the marker could differentiate into a distinct population of ILC3s found only in IBD samples. “CD62L ILCs with preferential differentiation capacity toward IL-22–producing ILC3s accumulated in the inflamed mucosa of patients with inflammatory bowel disease,” the researchers reported. “The discovery of naïve-like ILCs suggests an ILC differentiation process that is akin to naïve T-cell differentiation. Delineating the mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease.”

The scientists now hope to study if the presence and properties of immature intestinal ILCs can predict responses to drug treatment, and particularly medicines containing the active substances ustekinumab, infliximab, and tofacitinib, which are currently used to treat Crohn’s disease and ulcerative colitis, two of the most common IBDs.

“These studies are important since the right choice of effective treatment can reduce both personal suffering and societal costs,” said senior author Jenny Mjösberg, PhD, associate professor, department of medicine, Huddinge at Karolinska Institutet.

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