Scientists Rethink Overactive Immune System Treatments After Identifying Molecule That Triggers White Bloods Cells To Fight

Dendritic cells
NKT cells, crucial to our immune response, are activated by the newly discovered alpha-glycosylceramide molecules. Photo courtesy of Shutterstock

Scientists recently uncovered the roots of a crucial part of our immune system when they identified molecules that activate a subset of immune cells needed to fight infections. The molecules, which were known to be produced only by simpler life forms until now, open up new doors to understanding the  evolution of the mammalian immune system.

The discovery of the molecules provides a new basis for developing therapeutics aimed at managing conditions that result from an overactive immune system, such as type 1 diabetes. The findings, which have been published today in the journal Immunity, will also help to improve effectiveness of vaccines.

How Does The Immune System Work?

When a germ enters our body, specialized cells called dendritic cells activate the T and B cells to launch an attack against the invaders. They also activate a subset of T cells, called natural killer T (NKT) cells. NKT cells act as a bridge between innate immunity and acquired immunity by managing the functions of the dendritic cells, and also coordinate the responses of T- and B-type cells.

"Because of their dual functions, NKT cells are a bridge between the body's innate immunity, which is characterized by rapid but less specific responses to pathogens, and adaptive or acquired immunity, which is composed of specialized white blood cells that can remember past invaders," said study leader Luc Teyton in a statement.

It is known that NKT cells are activated by molecules known as glycolipids produced by dendritic cells. Specifically, a class of glycolipids called beta-glycosylceramides, also an important component of the nervous system, were thought to be involved. But previous attempts to test this through chemical assays always failed, since there was a confusion between beta-glycosylceramides and another chemically similar glycolipid, called alpha-glycosylceramide.

Attempts at synthetic production of the two molecules also gave rise to the same problem. As Teyton put it, "When you're making glycolipids, there is no completely faithful way of controlling the form that you're making. You're favoring the making of one, but you cannot say for sure that you don't have a small amount of the other form."

So the team came up with another method to test the molecules: a combination of biochemical and biological assays. By using custom-made antibodies, they first eliminated alpha-glycosylceramides from the test batches. When they were sure that they had only beta forms of the glycolipid, they tested it on NKT cells gathered from mice. To their surprise, the beta-glycosylceramides completely failed to activate the NKT cells.

To further make sure that they had the correct result, they used enzymes to digest molecular linkages found only on betaglycosylceramides with mice NKT cells inside test tubes. Surprisingly, the NKT cells were still being activated. They then disabled alpha-glycosylceramides inside live mice and found that not only did NKT cells fail to activate, but they disappeared altogether from organs such as the thymus, where NKT cells are produced.

The team had conclusive evidence that it was the alpha-glycosylceramides which activated the NKT cells.

These are surprising results, says the team. Until now it was thought that alpha-glycosylceramides were only present in bacterial cells that used it as a method to communicate with each other. But this finding suggests mammalian immune systems produce it, and they are an important part to maintaining health.

This discovery can be used to develop new therapeutics to manage autoimmunity that may be triggered as a result of overproduction of these molecules. They molecules can also be combined with antigens to create vaccines that elicit a faster and more efficient immune response.

"This opens up an avenue of new therapeutic approaches that we've never even thought about," Teyton said.

Source: Teyton L, Kain L,  Webb B, The identification of the endogenous ligands of Natural Killer T cells reveals the presence of mammalian alpha-linked glycosylceramides. Immunity. 2014.

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