Salk Institute researchers uncover protein that
influences the function of Tregs that can ultimately be used to
make immune-related therapies more effective, including for type 1
From left: Ruth Yu, Ye Zheng, Annette Atkins, Ronald Evans,
Nanhai He, Michael Downes, Weiwei Fan, Brian Henriquez.
Regulatory T cells (Tregs) are the traffic cops of the immune
They instruct other types of immune cells on when to stop and
when to go. Learning how to direct the activity of Tregs has
important implications for improving cancer immunotherapy as well
as developing better treatments for autoimmune diseases such as
rheumatoid arthritis and type 1 diabetes.
Now, a research team from the Salk Institute has uncovered for
the first time a protein that controls both the survival and
function of Tregs.
The discovery, published in the Proceedings of the
National Academy of Sciences, suggests ways to influence the
function of Tregs and ultimately to make immune-related therapies
"Tregs are at the crossroads of inflammation," says senior
Evans, Howard Hughes Medical Institute investigator and holder
of Salk's March of Dimes Chair in Molecular and Developmental
Biology. "If you have a lot of Tregs in the environment, they
weaken your immune response. If you have too few you go down the
road of chronic inflammation."
"Right now there are no good targets for controlling Tregs,"
says Nanhai He, a research associate in Evans' laboratory and the
study's first author. "This finding is very new and very important,
because it shows us the role of cellular metabolism in how these
immune cells function."
The protein the team studied is called Lkb1 (for liver kinase
B1). Kinases are enzymes that catalyze reactions inside cells.
Lkb1 was previously known to play a role in cell metabolism, but
until this study, investigators didn't know that it controls the
functions in the immune response of Tregs.
"When we talk about metabolism, most people think about factors
like what we eat and how much we exercise," says Annette Atkins, a
staff researcher in Evans' lab.
"But in this case, we're looking at the metabolism of individual
cells. By compromising the ability of these cells to make energy,
we see very profound autoimmune disorders."
In the current study, the team used mouse models that had
the Lkb1 gene knocked out in their regulatory T
The mice showed many symptoms of autoimmune disease and died
within a few weeks of birth.
Further examination revealed that the normal metabolic machinery
in the Tregs was disrupted. The cells had defective
mitochondria-cellular power stations-and depleted levels of ATP,
which is their most important fuel source.
"Through these observations, we determined that the Lkb1 pathway
is responsible for supplying Tregs with energy," says Ye Zheng, an
associate professor in Salk's Nomis Foundation Laboratories for
Immunobiology and Microbial Pathogenesis. "Without it, Tregs don't
have enough fuel to function."
"It turns out that Tregs require a lot of energy to do their
job, which is essentially to prevent other kinds of T cells from
attacking the body," adds Michael Downes, a Salk senior scientist.
"This is something that wasn't previously recognized, and it's an
The investigators say the findings have implications for both
cancer immunotherapy and therapy for autoimmune diseases.
In cancer, Tregs are recruited by tumors and prevent other types
of T cells, including cytotoxic T cells (also called CD8 cells)
from attacking and destroying cancer cells. "To boost cancer
immunotherapy, we'd like to find ways to block the Lkb1 pathway,"
Zheng explains. "The outcome of this inhibition would be an
increased immune response from other types of T cells, which would
help them to destroy tumors."
On the other hand, boosting the ability of Tregs to suppress
other types of immune cells could prevent autoimmunity, by
preventing these cells from attacking organs and other tissues.
Boosting the Treg population also has potential to avert immune
rejection after an organ transplant.
The investigators say that although Lkb1 itself is difficult to
target, they have already identified molecules downstream in the
signaling pathway that could be altered with drugs.
"These drugs could either inhibit or enhance the pathway,
depending on what we want them to do," He explains. Further
research from the team will focus on the development of such
Other researchers involved in the study were Weiwei Fan, Brian
Henriquez and Ruth Yu of Salk; and Christopher Liddle of the
University of Sydney.
This work was funded by the National Institutes of Health, the National
Institute of Environmental Health Sciences, the Leona M. and Harry
B. Helmsley Charitable Trust, the Foundation
Leducq and Ipsen/Biomeasure.