Scientists have found that T cells (immune cells
that help to protect the body from infections and
cancer) change the body’s metabolism when they are
activated, and that this activation actually leads
to changes in behavior.
It is currently known that individual T cells change
their metabolism to meet their energy needs after
being activated, but the systemic metabolic effect
of sustained activation of the immune system has
To understand the systemic effects, a group of
scientists from the RIKEN Center for Integrative
Medical Sciences in Japan and collaborators looked
at T cell activation in mice designed to lack a
surface receptor called PD-1, which is necessary for
inhibiting the activity of T cells.
T cells remain activated in mice without the
receptor, similar to those in the immune systems of
people with certain types of autoimmune disease.
In these mice, they found that amino acids
(molecules that are used to build proteins) were
depleted in the blood, and that they were increased
in the T cells themselves, implicating the T cells
in the change.
The team tracked and imaged amino acids in many
organs, and found that the depletion of amino acids
from the blood was taking place due to the
accumulation of amino acids in activated T cells in
the lymph nodes, showing that strong or long lasting
immune responses can cause metabolic changes
elsewhere in the body.
By analyzing the biochemistry of the brain, they
found that the systemic decrease in the amino acids
tryptophan and tyrosine in blood led to lower
amounts available in the brain, limiting production
of the neurotransmitters serotonin and dopamine.
These neurotransmitters affect emotions, motivation
and fear, for example serotonin is often a target of
drugs that combat depression.
The researchers found that their depletion in mice
without PD-1 resulted in behavioral changes
dominated by anxiety and exacerbated fear responses,
which could be remedied by providing a diet rich in
an essential amino acid.
This research, which was published in Nature
Immunology, required teamwork and collaboration to
link diverse fields of biology: immunology,
neuroscience and behavior, using cutting edge
metabolite measurements and imaging methods.
“Together these data indicate that excessive
activation of T cells causes a systemic metabolomic
shift with consequences that extend beyond the
immune system” says Michio Miyajima, one of the four
first co-authors of this study.
According to Sidonia Fagarasan, the leader of the
group, "We were fascinated to see that this
happens-as it revealed the power of the immune
system to influence many aspects of the body’s
physiology besides infection and immunity.
It will be interesting in the future to investigate
whether the trigger of fear and anxiety by T cell
activation is merely a side effect of the process,
or whether there is an evolutionary benefit of this
We would also like to further investigate these
changes, as the blockade of PD-1 is being
investigated as an anti-cancer therapy, and it is
important to understand if this could have
behavioral changes such as increases in anxiety.”
This research was supported by the Japan Agency for
Medical Research and Development–Core Research for
Evolutional Science and Technology (14532135 to
S.F.), Japan Agency for Medical Research and
Development (145208 and 16770835 to T.H.) and the
Cell Science Foundation (K.C). The work was done by
RIKEN in collaboration with Keio University, Kyoto
University, and other institutions.
For more information
Michio Miyajima, Baihao Zhang, Yuki Sugiura,
Kazuhiro Sonomura, Matteo M. Guerrini, Yumi Tsutsui,
Mikako Maruya, Alexis Vogelzang, Kenji Chamoto,
Kurara Honda, Takatoshi Hikida, Satomi Ito, Hongyan
Qin, Rikako Sanuki, Keiichiro Suzuki, Takahisa
Furukawa, Yasushi Ishihama, Fumihiko Matsuda, Makoto
Suematsu, Tasuku Honjo and Sidonia Fagarasan,
"Metabolic shift induced by systemic T cell
activation in PD-1-deficient mice perturbs brain
monoamines and emotional behavior", Nature
Immunology, doi: 10.1038/ni.3867
RIKEN Center for Integrative Medical Sciences