Linking the immune system with lipid metabolism

A team of researchers led by scientists at The Scripps Research Institute has discovered a family of proteins that connect the immune system to the body’s lipids – the fat molecules that are a major building block of the human body.

“This is the first time someone has shown how the immune system and lipid metabolism merge,” says Associate Professor Luc Teyton, M.D., Ph.D., of Scripps Research. Teyton is the lead author of the study.

In the study, Teyton and his colleagues were examining what is known as a natural killer (NK) T cell. NK T cells are key players in the immune system and have been implicated in autoimmune diseases, such as diabetes, and in cancer–although scientists have not yet discerned exactly how.

NK T cells are unusual in that they fall somewhere between innate and adaptive immunity. They arise in the thymus, and, as mature cells, they stimulate an adaptive immune response and regulate a range of disease states, including diabetes, cancer, and pathogenic infections.

Like other T cells, they express T cell receptors (TCR)–although without the normal antigenic variability. Classical immune recognition involves a process in which variable TCRs recognize various proteins–pieces of protein from foreign pathogens, for instance–when these are presented by “antigen presenting cells” via a molecule called the major histocompatability complex (MHC). MHC molecules are like the burglar alarms that warn the immune system that a pathogen is invading.

However, NK T cells also express the “NK” innate immune cell receptors and may have the ability to see some of the lipids that bacteria like Mycobacterium tuberculosis, the bacteria that cause tuberculosis, display on their outer surface. NK T cells become activated when they bind to a cell surface protein called CD1 that bears an unknown lipidic ligand.

Once the NK T cells bind to CD1, they become activated and begin to secrete a large amount of proteins like interferon-gamma and interleukin-4, which in turn activate helper T cells. The helper T cells then induce specific B cells to unload bursts of soluble antibodies into the bloodstream, and these antibodies ultimately deal with cancerous cells and pathogens.

“These [NK T cells] are the master keys for the regulation of the immune system,” says Teyton.

Critical Transfer Protein

Lipid binding to CD1 is not confined to the immune response, though, and endogenous human lipids seem to bind to CD1 as a way of maintaining normal bodily homeostasis.

A few years ago, Teyton was asking how the body loaded natural lipids onto CD1 molecules. He realized that there would have to be another protein inside cells that would transfer the lipid to the CD1 molecule, and so he searched on his computer for possible candidate proteins that could bind to lipids and transfer them onto CD1.

He found a family of genes that encode what are known as lipid transfer proteins, which were already well-characterized because they have been implicated in a number of neurological pediatric diseases. He began investigating whether any of these was the critical transfer protein he sought.

Indeed, one was.

Teyton and his colleagues found that if they removed the gene encoding for the protein prosaposin, they lost all NK T cells. This loss occurred because without prosaposin, the CD1 proteins were never loaded with the lipid, and therefore the NK T cells could not be selected in the thymus of the mutant mice. In addition, using recombinant forms of the saposins molecules, they demonstrated that saposin molecules could efficiently transfer lipids onto CD1d molecules.

Now the researchers are looking at which lipids bind to the CD1 molecules and how they are transported into the cell.

This work was done in very close collaboration with the laboratory of Dr. Albert Bendelac at the University of Chicago.

The research article “Editing of CD1d-Bound Lipid Antigens by Endosomal Lipid Transfer Proteins” is authored by Dapeng Zhou, Carlos Cantu III, Yuval Sagiv, Nicolas Schrantz, Ashok B. Kulkarni, Xiaoyang Qi, Don J. Mahuran, Carlos R. Morales, Gregory A. Grabowski, Kamel Benlagha, Paul Savage, Albert Bendelac, and Luc Teyton and appears in ScienceExpress, the online version of the journal Science on December 18, 2003.

The research was funded by the National Institutes of Health and the Cancer Research Institute.