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Scientists identify trigger for crucial immune system cell.

Scientists at The Scripps Research Institute (TSRI), Brigham Young University,  La Jolla Institute and the University of Chicago have identified the long-sought activating molecules for a rare but crucial subset of immune system cells that help rally other white blood cells to fight infection.  In the process, the team also uncovered a previously unsuspected link between the mammalian immune system and the communication systems of simpler organisms such as bacteria.

The opensource study, published ahead of print in the journal Immunity, could lead to novel therapeutic approaches for diseases such as type 1 diabetes that are the result of immune system overactivity, as well as new ways to boost the effectiveness of vaccines.

When a virus, bacteria or foreign substance invades the body, specialized cells known as dendritic cells present in the skin and other organs capture the trespassers and convert them into smaller pieces called antigens that they then display on their cell surfaces. White blood cells known as T and B cells recognize the antigens to launch very specific attacks on the invaders.

Dendritic cells also activate a specialized population of T cells known as natural killer T (NKT) cells. Once activated, NKT cells can commandeer the functions of dendritic cells to make them more effective and also recruit and 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 specialised white blood cells that can remember past invaders.

Previous studies indicated that NKT cells are activated by molecules known as glycolipids that dendritic cells produce and then display on their outer surfaces. It was widely assumed that the activating molecules were a class of glycolipids known as beta-glycosylceramides, an important component of nervous system cells.

However, this hypothesis had not been thoroughly examined, in part because there is no chemical test currently available to distinguish between two forms of the molecule that have slightly different configurations, beta-glycosylceramide and alpha-glycosylceramide. In addition, when scientists attempt to create either form synthetically for testing, there is always the possibility of small contamination of one by the other.

In the current study the team abandoned the chemical approach altogether. Instead, they combined a series of biochemical and biological assays to create a test that was sensitive enough to distinguish between the two different forms of glycolipids.  Biological assays are exquisitely sensitive to low amounts of otherwise unmeasurable molecules.

The scientists used custom antibodies to identify and eliminate alpha-glycosylceramides from their test batches. When the team was confident that their test batch contained only beta forms of the glycolipid, they tested it on NKT cells gathered from mice. To their surprise, however, nothing happened. Contrary to the conventional wisdom, the beta-glycosylceramides failed to activate the NKT cells causing the team to summise that they had used the wrong antibody.

Next, the team combined enzymes designed to digest molecular linkages found only on beta-glycosylceramides with mice NKT cells inside test tubes. Surprisingly, the NKT cells were still being activated.

Finally, when the team used antibodies to disable alpha-glycosylceramides inside live mice, not only did the NKT cells fail to activate, they disappeared altogether from organs such as the thymus, where NKT cells are produced.  These multiple lines of evidence strongly indicated that it was the alpha form of the glycolipids that were the triggers for NKT cells.  What the team thought was the contaminant turned out to be the activating molecule they were looking for.

The results were surprising for another reason. Until that moment, scientists did not think mammalian cells were capable of producing alpha forms of the glycolipids. The molecules were thought to exist only in bacteria and other simple organisms, which use them primarily as a means of communicating with one another. The findings thus suggest that the roots of a crucial part of the mammalian immune response are even more ancient than previously thought.

Now that scientists know that alpha-glycosylceramides are made by the human body and activate NKT cells, they might be able to exploit it to create new therapies. For example, researchers could use enzymes to reduce alpha-glycosylceramide levels in order to suppress an overactive immune response, which happens with diseases such as type 1 diabetes. Or they could combine the molecules with antigens to create vaccines that elicit a faster and more efficient immune response.

The team state that this opens up an avenue of new therapeutic approaches that they’ve never even thought about.

Source:  The Scripps Research Institute (TSRI)

 

The L363 Antibody Binds with Different Affinity to Both CD1-a-GalCer and CD1-a -GluCer Complexes but Does Not Recognize b-Glycosylceramide-CD1d Association.  Predicted L363 binding to glycosylceramides. In the crystal structure, L363 contacts a-GalCer with two H-bonds, G50 interacts with the axial 400-OH, and R32 is specific to the sphingosine chain (Protein Data Bank [PDB] ID 3UBX, left panel).  Modeling the interaction with a-GluCer illustrates the loss of the H-bond with G50, which as a result of equatorial rather than axial position of 400-OH, leads to weaker L363 binding affinity (middle panel). However, N31 and R32 together form a cap over the sugar and bind through van der Waals interactions, predominantly through N31. The upright positioning of b-GalCer (modeled with the crystal structure of mCD1d-sulfatide [PDB ID 2AKR]) would prevent L363 binding as a result of steric clashes (right panel).  The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian a-Linked Glycosylceramides.  Teyton et al 2014.
The L363 Antibody Binds with Different Affinity to Both CD1-a-GalCer and CD1-a-GluCer Complexes but Does Not Recognize b-Glycosylceramide-CD1d Association. Predicted L363 binding to glycosylceramides. In the crystal structure, L363 contacts a-GalCer with two H-bonds, G50 interacts with the axial 400-OH, and R32 is specific to the sphingosine chain (Protein Data Bank [PDB] ID 3UBX, left panel). Modeling the interaction with a-GluCer illustrates the loss of the H-bond with G50, which as a result of equatorial rather than axial position of 400-OH, leads to weaker L363 binding affinity (middle panel). However, N31 and R32 together form a cap over the sugar and bind through van der Waals interactions, predominantly through N31. The upright positioning of b-GalCer (modeled with the crystal structure of mCD1d-sulfatide [PDB ID 2AKR]) would prevent L363 binding as a result of steric clashes (right panel). The Identification of the Endogenous Ligands of Natural Killer T Cells Reveals the Presence of Mammalian a-Linked Glycosylceramides. Teyton et al 2014.

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