St. Jude Children’s Research Hospital scientists have discovered that
a protein widely known for suppressing tumor formation also helps
prevent autoimmune diseases and other problems by putting the brakes on
the immune response. The research was published recently online ahead of
print in the scientific journal Nature Immunology.
St.
Jude Children’s Research Hospital scientists show that the PTEN tumor
suppressor protein is essential for proper regulatory T cell function;
discovery offers new focus for improving treatment of autoimmune
diseases.
Researchers showed that the tumor suppressor protein PTEN is
essential for proper functioning of regulatory T cells. This small
population of white blood cells helps to maintain immune system balance
by suppressing specialized T cells called helper T cells that fuel
distinct parts of the immune response. The helper T cells investigated
in this study included type 1 T helper (Th1) and follicular T helper
(Tfh) cells.
The interplay between regulatory T cells and helper T cells is
crucial for both combating infections and for preventing misguided
immune attacks that lead to autoimmune diseases and other problems. But
details of how regulatory T cells control the diverse functions of
various helper T cells have been elusive. This study fills key gaps in
that understanding, particularly PTEN’s role. The work also identified a
new focus for research to improve treatment of autoimmune diseases.
PTEN is best known as one of the most frequently altered tumor
suppressor genes in human cancers, but loss of the protein has also been
tied to autoimmune problems. This study showed that is because PTEN is
required to maintain the stable population of regulatory T cells that
keeps the immune system in check.
"In humans we know that loss of PTEN leads to tumors. This
study highlights another role and shows that PTEN is also crucial for
proper functioning of regulatory T cells and prevention of autoimmune
diseases," said corresponding author Hongbo Chi, Ph.D., a member of the
St. Jude Department of Immunology. "In mice, the loss of just one copy
of the PTEN gene in regulatory T cells is sufficient to set the stage for autoimmune problems."
Working in specially bred mice, researchers showed that deleting the PTEN
gene in regulatory T cells was followed by a dramatic increase in the
number of Tfh and related cells. Tfh cells aid production of antibodies,
which combat infections. But when produced inappropriately, antibodies
can also drive autoimmune disorders like lupus. The mice in this study
developed kidney damage and immune changes associated with lupus.
Restoring PTEN to 50 percent of normal levels did not protect the mice
from inflammatory disease.
Researchers found evidence that Th1 cells influence the activity of
Tfh cells. Th1 cells produce the chemical messenger interferon gamma
that revs up the immune response. When researchers blocked interferon
gamma production in the specially bred mice, the number of Tfh cells
fell along with lupus-like immune abnormalities.
"We have identified a crucial role of PTEN in controlling Tfh cells
and autoantibody production. Additionally, by linking the role of PTEN
to Tfh cells, we have opened doors for further investigation of Tfh
related lymphomas," said co-first author Sharad Shrestha, a graduate
student in Chi's laboratory. Added co-first author Kai Yang, Ph.D., a
staff scientist in Chi’s laboratory: "These results reveal a hierarchy
of control that regulatory T cells use to simultaneously regulate Th1
and Tfh cells. We showed that Th1 production of interferon gamma is a
pre-requisite for the activity of Tfh cells."
The findings also yielded insight into a cell signaling pathway that
regulates many important functions, including T cell activity, in
response to changing conditions. This is the mTOR pathway, in which the
protein complexes mTORC1 and mTORC2 play central roles.
Investigators showed that deletion of PTEN in regulatory T
cells led to increased activity of mTORC2 but not mTORC1. When
scientists blocked mTORC2 activity in mice whose regulatory T cells
lacked PTEN, immune system balance and activity returned to
normal. “Our research establishes that the interaction of PTEN and
mTORC2 functions as a central pathway to maintain the stability of the
regulatory T cell population and to ensure their ability to control the
activity of Th1 and Tfh cells,” Chi said. The newly identified
PTEN-mTORC2 axis provides another target for efforts to develop better
treatments of autoimmune and other disorders.
The other authors are Cliff Guy, Peter Vogel and Geoffrey Neale, all of St. Jude.
The research was funded in part by grants (AI105887, AI101407,
CA176624, NS064599) from the National Institutes of Health; the American
Cancer Society, the Crohn’s and Colitis Foundation of America; the
Arthritis Foundation and ALSAC.
St. Jude Media Relations Contacts
Carrie Strehlau
desk (901) 595-2295
cell (901) 297-9875
carrie.strehlau@stjude.org
Summer Freeman
desk (901) 595-3061
cell (901) 297-9861
summer.freeman@stjude.org
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is leading the way the world
understands, treats and cures childhood cancer and other
life-threatening diseases. It is the only National Cancer
Institute-designated Comprehensive Cancer Center devoted solely to
children. Treatments developed at St. Jude have helped push the overall
childhood cancer survival rate from 20 percent to 80 percent since the
hospital opened more than 50 years ago. St. Jude is working to increase
the overall survival rate for childhood cancer to 90 percent in the next
decade. St. Jude freely shares the breakthroughs it makes, and every
child saved at St. Jude means doctors and scientists worldwide can use
that knowledge to save thousands more children. Families never receive a
bill from St. Jude for treatment, travel, housing and food—because all a
family should worry about is helping their child live. To learn more,
visit stjude.org or follow St. Jude at @stjuderesearch.