Vitamin D receptor defines 2 distinct lines of immune cells: Early study

Findings shed light on link between vitamin D and autoimmune diseases

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by Steve Bryson, PhD |

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The body has two distinct lineages of immune cells that can be distinguished by the presence or absence of the vitamin D receptor, a preclinical study reports.

The findings shed more light on how vitamin D fine-tunes immune responses and may help researchers better understand the link between vitamin D and autoimmune diseases, such as multiple sclerosis (MS).

“This suggests that vitamin D is regulating immune response by targeting some cells but not others,” Margherita Cantorna, PhD, study lead and professor of molecular immunology at Penn State University, said in a university press release.

Understanding the mechanisms underlying immune responses from vitamin D receptor-positive versus receptor-negative cells may support the development of immune-targeting vitamin D interventions, researchers noted.

The study, “Two lineages of immune cells that differentially express the vitamin D receptor,” was published in The Journal of Steroid Biochemistry and Molecular Biology.

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Vitamin D deficiency has been linked to increased MS risk

MS is an autoimmune disease marked by inflammation and damage to parts of the brain and spinal cord. While the exact cause of MS remains unknown, it is thought that various risk factors contribute to its development, including genetic susceptibility, infection, disease history, demographics, and environmental factors.

Vitamin D deficiency has been linked to an increased risk of MS, suggesting that the vitamin plays a role in preventing the development of the disease. However, clinical trials testing vitamin D supplements versus a placebo in MS patients have yet to show a definitive impact on disease activity and progression.

Among its many functions in the body, vitamin D is best known for regulating calcium absorption from the intestines. Its involvement in immune function is also well-established. Receptors for vitamin D have been found in various immune cell types, including monocytes, T-cells, and B-cells.

“Since 1983, it has been known that immune cells such as monocytes and activated T and B cells expressed the vitamin D receptor and are, therefore, vitamin D targets,” Cantorna said. “We set out to understand more about the mechanisms that regulate the immune system — how vitamin D affects these cells whose job it is to turn the immune response on and off.”

Using mouse models, Cantorna and her team discovered that vitamin D dampens immune activity following a response to infections.

“We learned by studying various infections in mice that vitamin D seems to help the immune system turn off after the infection is gone,” Cantorna said. “And that’s critical for recovery from infection because many infections’ lethality results from too much immune response — the inflammation caused by the infection lasts longer and is more severe if the immune response goes unchecked.”

“This discovery that vitamin D plays a subtle yet critical role in controlling immune response advanced our understanding of the role of vitamin D as a regulator of immunity,” Cantorna added.

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Sensitive test used to detect vitamin D receptors in immune cells

In the lab, her team used flow cytometry, a sensitive assay used to measure the characteristics of a population of cells, to find those that carry the vitamin D receptor at their surface. This work can be challenging because, unless activated, immune cells seem to produce low levels of the vitamin D receptor.

“It’s tricky with immune cells,” Cantorna said. “They express vitamin D receptors, but at very low levels compared to cells in other tissues …. To detect vitamin D receptors in immune cells, you need more sensitive assays.”

“To make identification even more challenging, most of the data show that the resting immune system has very low levels of the vitamin D receptor,” she noted. “Only a couple of days after an infection did immune cells actually express the vitamin D receptor. So receptor expression was regulated by the presence of an infection.”

In this report, researchers described two lines of immune cells, with and without vitamin D receptors. An examination of mouse tissue showed that some immune cells carry vitamin D receptors and are thus sensitive to the vitamin, while others do not and are insensitive to its immune-regulating effects.

The team particularly found that hematopoietic stem cells — the stem cells that give rise to all blood cells — as well as immune monocytes, macrophages, and neutrophils (immune cells that make up the first line of defense against infections) were nearly all positive for the receptor, “suggesting that essentially all of those innate cells are vitamin D targets,” the researchers wrote.

T-cells and innate lymphoid cells were also mostly vitamin D receptor-positive, which is consistent with vitamin D being able to regulate immune responses involved in autoimmunity, the team noted.

This discovery that vitamin D plays a subtle yet critical role in controlling immune response advanced our understanding of the role of vitamin D as a regulator of immunity.

Findings may help design vitamin D interventions that target immune system

While cells that are positive for the receptor increase its production when activated, the team found that T-cells negative for the vitamin D receptor in a resting state continued to be negative when activated.

Also, consistent with the lack of effect from vitamin D, these negative T-cells grew faster when activated and secreted more interferon gamma, an immune signaling molecule that further activates other immune cells.

Understanding the mechanisms that regulate the growth of cells with and without the vitamin D receptor may help design effective vitamin D interventions that target the immune system. For example, people with fewer immune cells producing the receptor may have poorer responses to vitamin D supplements.

“We’re also interested in tweaking those cells — or finding out if that’s possible,” Cantorna said. “What signals could increase vitamin D receptor expression in tissues and cells where we want to see the benefits of vitamin D? That knowledge will help advance us on the path of understanding the nuances of vitamin D as a regulator of immunity.”