Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 117, Issue 52, Pages 33446-33454Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2020619117
Keywords
anorexia; infection; T cells; FXR
Categories
Funding
- NCI Cancer Center Support Grants [P30 CA008748]
- NCI [U54 CA20997]
- NIH [R01 AI034206]
- Hilton-Ludwig Cancer Prevention Initiative (Conrad N. Hilton Foundation)
- Ludwig Center at the Memorial Sloan Kettering Cancer Center
- Hilton-Ludwig Cancer Prevention Initiative (Ludwig Cancer Research)
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Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.
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