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.

The Role of Short-Chain Fatty Acids and Bile Acids in Intestinal and Liver Function, Inflammation, and Carcinogenesis

“…Also the interaction between BAs and CD8 + T cells has been investigated insufficiently. Both the involvement of CD8 + T cells in controlling the BA synthesis by inducing cholangitis and the effect of FXR deletion on T cell fitness were described previously ( Glaser et al, 2019 ; Campbell et al, 2020a ). In addition, a recent study has revealed accumulation of CXCR6 + auto-aggressive CD8 + T cells in the liver of mice and patients suffering from NASH ( Dudek et al, 2021 ).…”

Control of immunity via nutritional interventions

“…Immunity and metabolism are mutually exclusive in that setting, with interferon-inducible immune response pathways upregulated at the expense of lipid metabolism (Han et al, 2017;Shulzhenko et al, 2011). The process of energy prioritization must be tightly regulated, with evidence indicating that T cell responses are physiologically dampened to limit the amount of energy they consume, thereby preventing excessive weight loss (Campbell et al, 2020). We will next discuss how the immune system integrates dietary cues to tune responses based on the nutritional status of the host and how trade-offs and priorities emerge when resources are severely limited.…”

The Role of Metabolic Dysfunction in T-Cell Exhaustion During Chronic Viral Infection

“…Then, glutamine is further deaminated into glutamate by glutamate synthase (GS) in a MYC-dependent pathway ( 31 , 49 ). Glutamate can be converted to α-ketoglutarate, which enters the tricarboxylic acid (TCA) cycle as an anaplerosis source to meet the biosynthetic and energy demands for T cells activation, especially under a glucose-restricted condition ( 52 ). Glutamate can also promote T cell activation by influencing the metabolism of other biomolecules, including nucleotide, fatty acids and amino acids ( 53 ).…”