Ann Pediatr Endocrinol Metab.  2024 Dec;29(6):356-364. 10.6065/apem.2448160.080.

Control of T-cell immunity by fatty acid metabolism

• Kim J
• Lee Y
• Chung Y

• KMID: 2563079
• DOI: http://doi.org/10.6065/apem.2448160.080

Abstract

Fatty acids play critical roles in maintaining the cellular functions of T cells and regulating T-cell immunity. This review synthesizes current research on the influence of fatty acids on T-cell subsets, including CD8⁺ T cells, T_H1, T_H17, T_reg (regulatory T cells), and T_FH (T follicular helper) cells. Fatty acids impact T cells by modulating signaling pathways, inducing metabolic changes, altering cellular structures, and regulating gene expression epigenetically. These processes affect T-cell activation, differentiation, and function, with implications for diseases such as autoimmune disease and cancer. Based on these insights, fatty acid pathways can potentially be modulated by novel therapeutics, paving the way for novel treatment approaches for immune-mediated disorders and cancer immunotherapy.

Keyword

Fatty acids; Fatty acid metabolism; Fatty acid signaling; Immunometabolism; T-cell differentiation

Figure

• 

  Fig. 1. Fatty acid metabolism in T cells. Free fatty acids enter immune cells either directly through simple diffusion or via CD36. Once inside the cell, fatty acids bind to proteins such as fatty acid-binding proteins (FABPs) that facilitate their transport. Alternatively, fatty acids can signal directly through cell surface receptors known as free fatty acid receptors (FFARs), where short-chain fatty acids (SCFAs) are known to act on FFAR2 and FFAR3, while MCFAs and LCFAs act on FFAR1 and FFAR4. Within the cell, (1) fatty acids enter the mitochondria via CPT1, where they undergo fatty acid oxidation (FAO), are broken down into acetyl-CoA, and enter the TCA cycle to produce adenosine triphosphate. (2) Fatty acids can also be incorporated into plasma membranes such as ER or cell membranes, regulating their fluidity or interaction with other cellular components. (3) Within T cells, fatty acids are modified by many different enzymes (e.g., ACC1, FAS, SCD) to form a wide variety of lipids such as phosphatidic acid (PA), lysophosphatidic acid (LPA), and phosphatidylinositol bisphosphate (PIP2). Fatty acids are modified by enzymes like desaturases to produce diverse lipid forms. All intermediates and products generated during intracellular fatty acid metabolism can epigenetically, structurally, or through specific signaling pathways, induce various changes in T cells. This positions fatty acids as novel mediators of immune diseases, including autoimmune disorders and cancer. SCFA, shortchain fatty acid; MCFA, medium-chain fatty acid; LCFA, long-chain fatty acid; cAMP, cyclic adenosine monophosphate; PLC, phospholipase C; IP3, inositol 1,4,5-trisphosphate; ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; SCD1, stearoyl- CoA desaturase 1; SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, poly-unsaturated fatty acid; LXR, liver X receptor; SREBP, sterol regulatory element-binding protein; PPAR-γ, peroxisome proliferator-activated receptor gamma; mTORC, mammalian target of rapamycin complex.

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  Fig. 2. Immunoregulation of CD4+ and CD8+ T cells by fatty acids. Dietary supplementation with ω-3 PUFAs decreases the frequency of TH1 cells and their effector cytokines in type 1 diabetes, and the serum lipid profiles are altered in SLE and RA patients. SCFA supplementation alleviates vancomycin-induced allergic asthma by downregulating TH2 immune responses, yet fatty acid immunometabolism remains largely unexplored in TH1 and TH2 cells. In TH17 cells, genes related to fatty acid metabolism (e.g., ACC1, ACLY, FASN), intracellular proteins (e.g., FABP, CD5L), and intracellular fatty acid composition critically regulate differentiation and effector functions. Treg-cell function is well-documented to be promoted by SCFAs and these cells actively utilize FAO for their energy needs. In TFH cells, CXCR5 expression is uniquely controlled by phosphatidylethanolamine (PE) and its de novo synthesis pathway, governed by the gene Pyct2. LCFA accumulation in the tumor microenvironment drives CD8+ T-cell dysfunction, but individual fatty acids or lipid subtypes that can potentiate CD8+ T cells are currently being researched. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; PUFA, poly-unsaturated fatty acid; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; IFN-γ, interferon-gamma; TNF-α, tumor necrosis factor-alpha; IL, interleukin; PCYT2, ethanolaminephosphate cytidylyltransferase; LCFA, long-chain fatty acid; ACC1, acetyl-CoA carboxylase 1; ACLY, adenosine triphosphatecitrate lyase; FASN, fatty acid synthase; FABP, fatty acid-binding protein; SFA, saturated fatty acid; RORγt, retinoic acid-related orphan receptor gamma t; SCD1, stearoyl-CoA desaturase 1; TGF-β, transforming growth factor-beta; PI, phosphatidylinositol; Acetyl-CoA, acetyl coenzyme A.

Reference

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