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FXR mediates T cell-intrinsic responses to reduced feeding during infection.


ABSTRACT: 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.

SUBMITTER: Campbell C 

PROVIDER: S-EPMC7776647 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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FXR mediates T cell-intrinsic responses to reduced feeding during infection.

Campbell Clarissa C   Marchildon Francois F   Michaels Anthony J AJ   Takemoto Naofumi N   van der Veeken Joris J   Schizas Michail M   Pritykin Yuri Y   Leslie Christina S CS   Intlekofer Andrew M AM   Cohen Paul P   Rudensky Alexander Y AY  

Proceedings of the National Academy of Sciences of the United States of America 20201214 52


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  ...[more]

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