T Cell Activation Leads To Behavioral Changes

T cells change the body’s metabolism when they are activated, and this activation actually leads to changes in behaviour, scientists from the RIKEN Center for Integrative Medical Sciences and collaborators have found.

It is known that individual T cells – immune cells that help to protect the body from infections and cancer — change their metabolism to meet their energy needs after being activated. But the systemic metabolic effect of sustained activation of the immune system has remained unexplored.

To understand the systemic effects, the researchers 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.

Immune Response Metabolic Changes

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.

The remaining question was whether this depletion of amino acids was actually having any systemic effect.

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 behavioural changes dominated by anxiety and exacerbated fear responses, which could be remedied by providing a diet rich in an essential amino acid.

“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 adaptation. 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,”

said Sidonia Fagarasan, the leader of the group.

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 & Sidonia Fagarasan
Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior
Nature Immunology (2017) doi:10.1038/ni.3867

Image: NIAID