NIAID Scientists Report Breakthrough Discoveries on Innate Lymphoid Cell Function

NIAID Now | January 23, 2018

Activated ILC2s in lymphatic vessels in the mouse small intestine. Different proteins are highlighted in red (KLRG1), green (EpCAM), blue (CD3) and cyan (Lyve-1). See below for the full video visualization.

Credit: NIAID

Two recent studies conducted by NIAID scientists shed light on previously unknown functions of a category of immune cells called innate lymphoid cells (ILCs). Only characterized in the past decade, these cells have features of both innate immune cells and adaptive immune cells.

Innate immune cells respond immediately to an infection but cannot recognize or specifically differentiate among foreign invaders, whereas adaptive immune cells are slow to react, but their response is more targeted: T cells and B cells of the adaptive immune system can recognize and neutralize specific pathogens. ILCs respond quickly to infection and cannot recognize pathogens, but they have some similar functions as helper T cells. However, exactly how similarly ILCs and adaptive T cells function in the body is unresolved, and it is unclear whether ILCs function in a tissue-resident manner or circulate among sites.

In a study published Jan. 5 in Science, NIAID scientists and colleagues from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Cornell University and the United States Department of Agriculture demonstrated that certain ILCs once thought to be tissue-resident can move among organs, such as the lungs or intestine, during infection.

They discovered this by performing a series of experiments in mice and using advanced imaging techniques to monitor ILC activation and movement. Prior studies show that following a helminth (parasitic worm) infection, inflammatory group 2 ILCs (ILC2s) are induced in multiple tissues in mice—lung, liver, lymph nodes and spleen. However, it was unclear if the cells moved among these tissue sites or were induced in place at multiple locations. The new experiments show that inflammatory ILC2s originate in the gut, enter lymphatic vessels, circulate in the bloodstream and can migrate to other organs to help fight infection. Until now, scientists believed that only adaptive immune cells could perform these functions. The findings suggest that the adaptive cells actually inherited this behavior from ILCs, which are thought to be evolutionarily older.

The results have also prompted investigators to call for re-evaluating the mode of action of the immunosuppressive drug FTY720, commonly used to treat multiple sclerosis. Experts previously believed the drug worked solely by trapping adaptive immune cells in secondary lymphoid sites. However, the NIAID-led experiments showed that it also blocked movement of ILC2s. The findings open new prospects for treatment of conditions in which ILCs contribute to disease, such as autoimmune and inflammatory diseases, according to the authors. They also note the field will need to examine if other types of ILCs can migrate and if so, the role this migration plays in host defense and autoimmune diseases.

In a related study published Jan. 22 in Nature, NIAID investigators from various labs and colleagues from the National Institute of Diabetes and Digestive and Kidney Diseases and the University of Washington School of Medicine discovered that ILCs and helper T cells, previously thought to have redundant functions, operate sequentially and in distinct ways.

Specifically, investigators sought to learn how group 3 ILCs and helper T cells each contribute to shaping and maintaining the gut microbiome using a mouse model. Recently, scientists have been working to better understand how certain changes in the microbiome affect health. For example, research shows that an underdeveloped microbiome is associated with severe nutritional abnormalities.

In mice specially bred to lack helper T cells, researchers found extensive and persistent evidence of a certain protein signature in group 3 ILCs indicating cytokine activation. However, in immune-competent mice, this protein signature was only transiently activated in young mice, then extinguished as helper T cell immunity developed and matured. Investigators found that without T cells, persistent group 3 ILC activity can have negative effects on the host, including an impaired ability to metabolize fats.

“Taken together, our results provide increased understanding of how the innate and adaptive immune systems act sequentially on the developing gut microbiota to establish a balanced commensal state supporting normal tissue function,” the authors note. They also explain that the study has important implications for understanding whether gut microbes contribute to metabolic disease only in a direct manner through their biochemical activities, or if they affect the host by changing the immune state that in turn alters how nutrients are handled.


Y Huang et al. S1P-dependent interorgan trafficking of group 2 innate lymphoid cells supports host defense. Science DOI: 10.1126/science.aam5809 (2018).

K Mao et al. Innate and adaptive lymphocytes sequentially shape the gut microbiota and lipid metabolism. Nature DOI: 10.1038/nature25437 (2018).

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