Linking the Immune System with Lipid Metabolism
By Jason Socrates
Bardi
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, 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.
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