A team of scientists at the University of California, San Francisco and
Compugen, Ltd. has discovered a new molecule of the immune system—a member
of a family of proteins called chemokines which recruit the body’s army of
defensive immune cells to sites of invasion. The new chemokine is only the
second one ever detected that is “tethered” within the membrane of cells rather
than being made in a diffusable form.
The research team used the chemokine as a molecular probe to identify its
receptor. Although its association with a chemokine was a discovery, the
receptor turned out to be one that had already been isolated by other
researchers in cell studies as one of the receptors exploited by invading HIV
viruses to gain entry into human cells.
The novel molecule was identified by researchers at the genomics and proteomics
research company Compugen, and its biological role was described by UCSF
scientists led by Jason Cyster, PhD, an investigator in the Howard Hughes
Medical Institute and assistant professor of microbiology and immunology at
UCSF. Cyster is senior author on a paper reporting the research in the October
issue of Nature Immunology, co-authored by all the researchers.
In experiments with mouse tissues, the UCSF scientists determined that the
novel chemokine, which they named CXCL16 (for 16th chemokine of the CXC
subfamily) is produced by cells within the spleen and lymph nodes—including
the so-called dendritic cells which help trigger immune responses—and also
by cells in the spleen’s red pulp.
Cytotoxic CD8 T cells, known for the ability to kill virally infected cells,
were found to express the chemokine receptor and to be able to migrate towards
a source of the chemokine. The researchers speculate that CXCL16 made by
dendritic cells might be important in helping activate CD8 T cells to make them
into fully functional killer cells. CXCL16 was also detected in some
non-lymphoid tissues, including small intestine, lungs, liver and kidney, and
in these sites it may help the activated CD8 cells carry out their killer
function during infections.
In addition to CD8 T cells, the receptor was found on subpopulations of CD4 T
cells, including a specialized population of CD4 T cells that live in the gut
and that are known as intra-epithelial T cells. Cyster suggests that the
chemokine may help restrain these specialized lymphocytes within the mucosa,
ready to fight invaders. Mucosal surfaces are a port of entry for the HIV
virus, and high expression of CXCL16 in the mucosa might influence the ability
of infecting HIV particles to utilize the CXCL16 receptor as a co-receptor.
Another specialized type of T cell, the Natural Killer T cell, was found to
have high expression of the receptor. Others have shown an important role for
these cells in responding to infections in spleen and liver, both sites where
the chemokine is made.
Known by three names including Bonzo, the receptor had been termed an “orphan
receptor” since its natural partner - which turns out to be the new chemokine
—had not been known. Now that its link with a chemokine has been identified,
the scientists have renamed the receptor according to accepted nomenclature.
Less flashy than Bonzo, the receptor’s new name is CXCR6.
The chemokine was identified using Compugen’s LEADS algorithm-driven drug
discovery platform that uses large-scale analysis of expressed human DNA to
find new sequences similar to those already known in other protein families.
This approach led to identification in public databases of a human gene that
resembled the chemokine family of molecules. The similarity was extremely low,
however, and it was likely for this reason that the sequence had laid in the
public database unrecognized as a candidate chemokine by researchers using
established sequence-alignment tools.
First author on the Nature Immunology paper is Mehrdad Matloubian, MD, PhD, a
post-doctoral researcher working with Cyster at UCSF. Compugen scientists
collaborated on the paper, along with Jay Ryan, MD, PhD, assistant professor
of immunology at UCSF and a physician at the Veterans Administration Medical
Center in San Francisco.
The UCSF research was funded by the NIH, the Packard Foundation and a UCSF
Molecular Medicine Training Program.
Compugen (Nasdaq:CGEN) is a publicly traded company.