Nutrient and Metabolic Sensing in T Cell Responses

Abstract

T cells play pivotal roles in shaping host immune responses in infectious diseases, autoimmunity, and cancer. The activation of T cells requires immune and growth factor-derived signals. However, alterations in nutrients and metabolic signals tune T cell responses by impinging upon T cell fates and immune functions. In this review, we summarize how key nutrients, including glucose, amino acids, and lipids, and their sensors and transporters shape T cell responses. We also briefly discuss regulation of T cell responses by oxygen and energy sensing mechanisms.

Keywords: T cell response; amino acid; energy; glucose; lipid; oxygen.

Figure 1

Glucose sensing shapes T cell immune responses. Glucose transporter 1 (Glut1) transports glucose into T cells to fuel glycolysis. The generation of effector T cells, including T_H1, T_H2, T_H17, and T_FH cells, is dependent on Glut1 expression and glycolytic metabolism. While Glut1 expression and glycolysis promote T_reg cell proliferation, they impair T_reg cell lineage stability and suppressive function. Thus, Glut1 expression provides a key mechanism to shape T cell responses. Glycolysis also promotes the formation of effector memory CD8⁺ T cells (T_EM). TCR and CD28 co-stimulation potently induces Glut1 expression, while the translocation of Glut1 from the cytoplasm to T cell surface is induced by various stimuli, including TCR-CD28, IL-7, and insulin.

Figure 2

Amino acid sensing modulates T cell responses. Antigen-driven activation of T cells through TCRs upregulates expression of many amino acid transporters, including the leucine and glutamine transporters LAT1, ASCT2, and CD98. LAT1 associates with CD98, forming a bidirectional transporter for leucine and glutamine. The intracellular sensors of leucine and glutamine in T cells remain unknown. mTORC1 is activated downstream of intracellular amino acids, leading to the regulation of CD4⁺ T cell differentiation (T_H1 and T_H17) and CD8⁺ T cell effector responses. Elevated intracellular l-arginine levels promote effector CD8⁺ T cell anti-tumor immunity and effector CD4⁺ T cell IFN-γ production and survival. Although the intracellular mediators critical for arginine sensing are unclear, three potential sensors are BAZ1B, PSIP1, and TSN.

Figure 3

Fatty acid (FA) and cholesterol sensing in T cell immune responses. (A) FA metabolism and sensing serve multiple roles in T cell biology. Short-chain fatty acids (SCFAs) diffuse passively or are transported into cells by G-protein-coupled receptors. SCFAs can inhibit histone deacetylases and induce T_H1 and T_H17 cell differentiation and IL-10 production. De novo FA synthesis is required for T_H17 generation. Intracellular FAs are recognized by peroxisome proliferator-activated receptors (PPARs). Expression of PPARγ is important for visceral adipose tissue T_reg cell accumulation and function, while antagonizing PPARγ by chemical drug promotes T_H17 development. (B) Cholesterol and cholesterol sulfates regulate T cell receptor (TCR) nanoclustering and signaling within the T cell. After stimulation of TCRs, T cells upregulate the cholesterol biosynthesis pathway through the SREBP/SCAP axis. This increase in cholesterol biosynthesis is important for acquiring T cell effector function. Additionally, intracellular sterols serve as ligands for intracellular receptors and transcription factors, such as liver X receptor (LXR) and RORγt to modulate T_H17 development.

Figure 4

Oxygen sensing orchestrates T cell immune responses. In oxygen-replete environments, such as in the lung, prolyl-hydroxylase domain (PHD) proteins sense high levels of cellular oxygen. Activated PHD proteins establish immune tolerance in the lung by inducing hypoxia-inducible factor 1α (HIF1α) degradation to promote T_reg cell and inhibit T_H1 cell differentiation. Hypoxia induces HIF1α expression, which regulates the reciprocal generation of T_H17 and T_reg cells and antagonizes T_H1 cell differentiation. HIF1α also temporally regulates Tr1 cell differentiation. HIF1α-dependent upregulation of S-2-hydroxyglutarate (S-2HG) enhances anti-tumor CD8⁺ T cell responses.

Figure 5

AMP-activated protein kinase (AMPK) and energy sensing dictate T cell immunity. AMPK is activated by the increased AMP to ATP ratio, which indicates energy deprivation. AMPK functions as a master regulator of cellular metabolism to preserve cellular energy homeostasis. AMPK activity is required for CD8⁺ T cell survival during infection and in tumor microenvironment. The accumulation of T_H1 and T_H17 cells in the colon is also dependent on AMPK activity. Aberrant AMPK activation is linked to impaired T_FH cell generation and CD4⁺ T cell senescence.