Cellular metabolism regulates the differentiation and function of T-cell subsets

Abstract

T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes-lipids, glucose, and amino acids-in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of "editing" metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.

Keywords: CD4+ T cells; CD8+T cells; Immunometabolism; Metabolism; T cell differentiation.

Fig. 1

Regulation of T cell activation and subset differentiation and function by lipid metabolism. A The length of the fatty acid chain influences CD4 + T cell differentiation. Furthermore, Treg cells and Th17 cells employ distinct strategies to obtain fatty acids (i.e., importing exogenous fatty acids or synthesizing fatty acids). The IL-6-STAT3 signaling pathway is expected to play a key role in the decision-making between these two strategies. In addition, the sterol supply not only provides essential substrates for T cell clonal expansion but also modulates Th17 differentiation through the LXR pathway. B Fatty acid oxidation promotes memory CD8 + T cell formation. The AA-PGE2 pathway suppresses CD8 + T cell effector function. Endogenous cholesterol synthesis supports CD8 + T cell activation and proliferation. Supplementation with cholesterol rescues CD8 + T cell proliferation with defects in cholesterol synthesis. FAs fatty acids, LXR liver-X receptor, AQP9 aquaporin-9, AA arachidonic acid, PGE2 prostaglandin 2. Images were created with Biorender.com, with permission

Fig. 2

The glucose metabolism network regulates CD4+ and CD8 + T cell subset differentiation and function. The signaling network, which is composed of glucose transporters, glycolytic enzymes, and glycolysis-related intracellular signaling hubs and surface receptors, modulates T cell differentiation and function. These transporters, enzymes, signaling hubs, and surface receptors, many of which are regulated by TCR activation, not only support T cell glycolysis and bioenergetics but also regulate signal transduction, the epigenetic landscape, and T cell subset differentiation. CTLA-4 cytotoxic T-lymphocyte-associated protein 4, TSC1 tuberous sclerosis complex 1, PTEN phosphatase and tensin homolog. Images were created with Biorender.com, with permission

Fig. 3

Amino acid metabolism modulates T cell survival and lineage commitment. A T cell activation increases the expression of amino acid transporters that import glutamine and arginine. Glutamine catabolism plays a crucial role in regulating the differentiation of naïve CD4 + T cells into Th1 cells, Th17 cells, or Treg cells. Excessive serine accumulation leads to mTOR hyperactivation and impairs the suppressive function of Treg cells. Arginine catabolism fuels polyamine biosynthesis and is necessary for maintaining CD4 + T cell subset identity. B The glutamine-glutamate-α-KG pathway shapes the epigenetic landscape, posttranslationally modifies proteins (i.e., glutarylation), and removes toxic ammonia in CD8 + T cells. CD8 + T cells require methionine and its downstream metabolite SAM to regulate histone methylation, STAT5 expression, and antitumor responses. Serine and glycine metabolism fuels one-carbon metabolism, glutathione generation, and de novo sphingolipid synthesis in CD8 + T cells. Tryptophan depletion or supplementation with its downstream product kynurenine inhibits T cell proliferation. Arginine metabolism promotes the activation and survival of antitumor CD8 + T cells. Arginine methylation in Sm proteins facilitates signal transduction by regulating pre-mRNA splicing of IL2rg and JAK3. α-KG α-ketoglutarate, GAB γ-aminobutyrate, GSH glutathione, Kyn kynurenine, 5-HTP 5-hydroxytryptophan. Images were created with Biorender.com, with permission