Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior

Abstract

T cells reorganize their metabolic profiles after being activated, but the systemic metabolic effect of sustained activation of the immune system has remained unexplored. Here we report that augmented T cell responses in Pdcd1 mice, which lack the inhibitory receptor PD-1, induced a metabolic serum signature characterized by depletion of amino acids. We found that the depletion of amino acids in serum was due to the accumulation of amino acids in activated Pdcd1 T cells in the lymph nodes. A systemic decrease in tryptophan and tyrosine led to substantial deficiency in the neurotransmitters serotonin and dopamine in the brain, which resulted in behavioral changes dominated by anxiety-like behavior and exacerbated fear responses. Together these data indicate that excessive activation of T cells causes a systemic metabolomic shift with consequences that extend beyond the immune system.

Altered tryptophan metabolism is associated with pediatric multiple sclerosis risk and course

“…This process leads to a systemic decrease in the serum amino acid levels and eventually, cerebral deficit in several key neurotransmitters. These metabolic alterations are associated with behavioral changes in the animals 32. Alternatively, decreased serum Trp could be caused by alterations in human endogenous Trp metabolism (kynurenine metabolic pathway) or altered gut microbial Trp metabolism.…”

The metabolic spectrum of memory T cells

“…When considering these factors in the context of an effector T‐cell immune response, it is interesting to note that many of these are influenced by, or act as, sensors for nutrient availability. Robust T‐cell responses can result in systemic changes in metabolite concentrations . It is conceivable, therefore, that in addition to changes in growth factor and cytokine signaling, a more intense effector response could also contribute to memory T‐cell development.…”

Translating In Vitro T Cell Metabolic Findings to In Vivo Tumor Models of Nutrient Competition

“…For example, enhancing tumor glycolysis is sufficient to decrease available glucose for T cells, but may also create a better environment for tumor associated macrophages and T regulatory cells (Angelin et al, 2017; Chang et al, 2015; Netea-Maier et al, 2018). In addition, simply increasing T cell activity is sufficient to modulate metabolites in the serum of mice, and the effects of these changes on other cell types is not understood (Miyajima et al, 2017). Future studies must work to better distinguish mechanisms of metabolic immune interventions to provide mechanistic understanding of immunometabolism (Fig 2A).…”