Lipid (fat) molecules can function as chemical couriers, taking messages from tissue to tissue, organ to organ as part of the body’s immune defense guidance system. But in certain diseases such as multiple sclerosis (MS), the courier service may go awry.
One such lipid molecule, called sphingosine 1-phosphate (S1P), was found to dictate the amount of time immune cells spend in the lymph nodes, where they reside, before entering into circulation when recruited into other tissues in the body.
The researchers say these findings point to new uses of medications that target S1P signaling.
The study reporting the findings is titled “Monocyte-derived S1P in the lymph node regulates immune responses” and was published in Nature.
Previous studies have shown that the immune system regulates the concentration of S1P in order to draw cells to the right locations. These targeted cells have receptors for S1P, and thus can be guided through S1P concentrations into other areas and structures.
Tissues in general have relatively low levels of S1P compared with blood and lymph. This different gradient in concentration allows immune cells such as T-cells to traffic from lymph nodes into circulation.
Now, a team of researchers at New York University (NYU) Langone Medical Center asked whether the concentration of S1P in lymph nodes changes during an immune response.
Using a series of experiments in mice, the researchers were able to show that the concentration of S1P in the lymph nodes increases during an immune response, and that monocytes — a type of immune cell — are an important source of this S1P.
“Our research shows a larger role for sphingosine 1 phosphate in coordinating immune defenses in response to infection and inflammation,” Audrey Baeyens, PhD, the study’s first author, said in an NYU Langone Health press release.
While previous studies showed that S1P is produced by cells attached to lymph nodes, now researchers found that monocytes in circulation also produce S1P when mice are infected with a virus. In turn, this may have an effect on the migration of immune T-cells — cells involved in the immune response against infection.
Specifically, it is known that if S1P levels in the lymph nodes increase, then “T-cells should stay longer in the lymph nodes, because the increased levels of S1P in the lymph nodes would counter lymph S1P directing exit,” the researchers wrote.
In fact, the team found that in mice in which S1P production is impaired, approximately 50% of T-cells exited the lymph nodes compared with 20% in lymph nodes from control mice, or those with no S1P production impairment.
These “trapped” T-cells in lymph nodes have a longer time to mature and become more lethal. Such mature T-cells can more effectively attack cells infected by viruses — but they also are more powerful when assailing healthy cells in the case of autoimmune diseases like MS.
Therefore, the researchers also measured the concentration of S1P and one of its receptors (S1PR1) in mice with experimental autoimmune encephalomyelitis (EAE), a widely used model for studies of MS. At the onset of disease symptoms, the level of T-cell surface S1PR1 in lymph nodes was reduced, consistent with the increased concentration of S1P.
“Increased levels of S1P prolonged the residence time of T-cells in the lymph nodes and exacerbated the severity of experimental autoimmune encephalomyelitis in mice,” the researchers wrote. “This finding suggests that residence time in the lymph nodes might regulate the differentiation of T-cells, and points to new uses of drugs that target S1P signalling.”
In fact, the importance of S1P signaling has led to the development of several therapies, including Gilenya (fingolimod), an oral treatment marketed by Novartis and approved by the U.S. Food and Drug Administration for patients with relapsing forms of MS.
Therapies that block S1P, like Gilenya, act by preventing immune cells from exiting the lymph nodes.
“Manipulation of the residence time in lymph nodes with the many drugs that target S1P signalling may be advantageous in some settings,” the researchers wrote.
However, after stopping treatment with these therapies, there is a high risk for disease relapse, which can be severe. The researchers said this occurs because T-cells are then freed from lymph nodes and can attack the body’s nerves — a key trait of MS.
“One devastating side effect of multiple sclerosis treatment with fingolimod, which targets four of the five S1P receptors, is severe disease rebound after drug withdrawal; we speculate that this may be due to the extended retention of T cells in the lymph nodes, inducing stronger activation,” the scientists wrote.
The team now plans to further analyze the associations between the levels of S1P and immune responses, namely T-cell maturation and how different maturation times can strengthen or weaken the overall immune response.
“While further testing is needed, our findings raise the prospect of controlling levels of S1P to either boost or diminish the body’s immune response, as needed,” Baeyens concluded.
That will include looking for new ways to use existing therapies, the researchers said.
“Now that we have a better understanding of sphingosine 1 phosphate inhibition, we can work on finding new uses for this class of medications, perhaps by manipulating the time T cells spend in the lymph nodes,” said Susan R. Schwab, PhD, the study’s senior investigator and a member of Skirball Institute of Biomolecular Medicine at NYU Langone.
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