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

Clarissa Campbell, Francois Marchildon, Anthony J. Michaels, Naofumi Takemoto, Joris van der Veeken, Michail Schizas, Yuri Pritykin, Christina S. Leslie, Andrew M. Intlekofer, Paul Cohen, Alexander Y. Rudensky

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33446-33454
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number52
DOIs
StatePublished - Dec 29 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Anorexia
  • FXR
  • Infection
  • T cells

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